bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒11‒22
thirty-nine papers selected by
Joanna Zawacka-Pankau
University of Warsaw

  1. Front Genet. 2020 ;11 566266
    Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, Hasselby JP, Wikman F, Okkels H, Skytte AB, Nilbert M, Wadt K, Gerdes AM, van Overeem Hansen T.
      A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.
    Keywords:  RPS20; early onset colorectal cancer; familial cancer; gene panel analysis; hereditary colorectal cancer; oligogenic inheritance
  2. Front Oncol. 2020 ;10 568911
    Xu T, Zhang Y, Zhang J, Qi C, Liu D, Wang Z, Li Y, Ji C, Li J, Lin X, Hou T, Liu H, Zhang L, Han-Zhang H, Shen L, Wang X.
      Background: Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC.Methods: 330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed.
    Results: Of the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-β pathway (p = 0.023) were associated with unfavorable OS in EO mCRC.
    Conclusions: Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.
    Keywords:  early onset colorectal cancer; genomic alternation; next generation sequencing; prognosis; susceptibility gene
  3. Transl Androl Urol. 2020 Oct;9(5): 2430-2440
    Schneider KW, Cost NG, Schultz KAP, Svihovec S, Suttman A.
      Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the location or the pathology of the sarcomas. Therefore, there are limited data on genitourinary specific associations with certain genetic syndromes. We summarize, here, the primary differential considerations for rhabdomyosarcoma of the genitourinary system. Primary considerations include DICER1 pathogenic variation, Li-Fraumeni syndrome, constitutional mismatch repair deficiency, mosaic variegated aneuploidy, neurofibromatosis type 1, Noonan syndrome, other RASopathies, Costello syndrome, and Beckwith-Wiedemann syndrome. Some conditions may present with specific pathological, clinical and/or family history features, but for others, the genitourinary tumor may be the only presenting sign at the time of diagnosis. Genetic evaluation with counseling and/or testing may help identify an underlying tumor predisposition. This manuscript serves as an introduction to germline considerations for children with genitourinary rhabdomyosarcoma.
    Keywords:  Genetics; cancer predisposition; genetic counseling; genitourinary; germline; rhabdomyosarcoma; syndrome
  4. Eur J Gastroenterol Hepatol. 2020 Nov 17.
    Di Leo M, Zuppardo RA, Puzzono M, Ditonno I, Mannucci A, Antoci G, Russo Raucci A, Patricelli MG, Elmore U, Tamburini AM, Albarello L, Azzolini F, Bonura GF, Esposito D, Fanti L, Notaristefano C, Viale E, Perea J, Testoni PA, Rosati R, Cavestro GM.
      BACKGROUND AND OBJECTIVES: Early-onset colorectal cancer (eoCRC), defined as colorectal cancer (CRC) before the age of 50 is increasing in incidence. We evaluated exogenous and endogenous risk factors, and clinical features of eoCRC, compared to late-onset CRC (loCRC).METHODS: In this retrospective case-case study, patients were prospectively enrolled from 2015 to 2018. We collected clinical features (age, sex, time from symptom onset to diagnosis, symptoms, family history, smoking and alcohol habits, diabetes, BMI, and genetic analysis) and tumor characteristics. Independent risk factors for eoCRC and odds ratios (ORs) were identified.
    RESULTS: Fifty-four eoCRCs and 494 loCRCs were enrolled. Patients with eoCRC experienced longer delay time from symptom onset to diagnosis: 40.7% were diagnosed within 6 months from symptoms onset, compared to 85.6% of patients with loCRC (P < 0.0001). They differed for sex, presence of symptoms, family history, smoking habit, alcohol intake, and BMI. Rectal localization was more closely associated with eoCRC (64.8%) than loCRC (34.5%, P < 0.0001). Family history of CRC was associated with eoCRC (OR = 8.8). When family history occurred with hereditary cancer syndromes, the OR for eoCRC increased to 21.
    CONCLUSION: In young adults with alarming symptoms, CRC must be suspected to avoid delay time from symptom onset to diagnosis and genetic risk assessment has to be evaluated. Smoking habits, alcohol intake, and BMI are not associated with eoCRC.
  5. Am J Transl Res. 2020 ;12(10): 6689-6693
    Yang D, Han X, Li D, Cui S, Liu S, Wu X, Dai Z.
      OBJECTIVES: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition, mostly caused by germline TP53 mutations. Lung adenocarcinoma (ADC) has been identified as the most frequent LFS-related cancer outside the common LFS core spectrum. EGFR-kinase domain duplication (KDD) is rare in lung cancer and the effective therapy for LFS patients with EGFR-KDD mutated ADC is unclear. This study reports the first case of a TP53-mutated LFS patient with confirmed family history, developing advanced lung ADC harboring EGFR-KDD.MATERIALS AND METHODS: The patient's lung tumor, lymph nodes, liquid biopsies and germline control sample at various disease stages were subjected to next-generation sequencing (NGS). The TP53 germline mutation was confirmed using the peripheral blood of the patient's relatives by Sanger sequencing.
    RESULTS: A rare EGFR-KDD somatic mutation that was missed in the routine EGFR hotspots test, and a TP53-E285K temperature-sensitive germline mutation were identified by NGS. The patient was diagnosed with breast cancer in 2006 and her family cancer history review revealed that seven out of 13 relatives were diagnosed or died from LFS-spectrum cancers before the age of 45 years. Three of the six relatives were positive for the TP53-E285K germline mutation. This patient received multi-line chemotherapy followed by anlotinib, a multi-target tyrosine kinase inhibitor, upon the identification of EGFR-KDD, and achieved an overall survival of 18 months.
    CONCLUSIONS: Our study highlights the importance of NGS in discovering rare genetic alterations to guide treatment decision-making, and provides meaningful insight into the potential treatment options for LFS patients with EGFR-KDD mutations.
    Keywords:  EGFR-KDD; Li-Fraumeni syndrome; TP53 temperature-sensitive mutation; lung adenocarcinoma; next-generation sequencing
  6. J Gastroenterol. 2020 Nov 18.
    Curtin BF, Gamble LA, Schueler SA, Ruff SM, Quezado M, Miettinen M, Fasaye GA, Passi M, Hernandez JM, Heller T, Koh C, Davis JL.
      BACKGROUND: Germline inactivating variants in the CDH1 tumor suppressor gene impart an elevated lifetime risk of diffuse gastric cancer. The current endoscopic surveillance method depends upon random gastric biopsies for early cancer detection.METHODS: Asymptomatic adults with pathogenic or likely pathogenic CDH1 variants referred for endoscopic gastric cancer surveillance were included in this retrospective cohort. Upper gastrointestinal endoscopy was performed according to the consensus Cambridge method, in the early period, or a systematic (Bethesda) protocol as part of an ongoing natural history study. The primary outcome measure was cancer detection.
    RESULTS: Collectively, 135 endoscopic surveillance procedures were performed in 120 patients. Twenty-six (19%, 26/135) procedures were performed using Cambridge method and 109 (81%) using the Bethesda protocol. Gastric signet ring cell carcinomas were detected in 15% (4/26) using the Cambridge method and 36% (40/109) using the Bethesda protocol (p < 0.05). Almost half (44.2%, 53/120) of patients later elected for prophylactic total gastrectomy, of whom 51 (96%, 51/53) had a signet ring cell carcinoma (T1a) discovered by histopathology. On a per endoscopy basis, the false-negative rates of detection using Cambridge method and Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively (p < 0.01).
    CONCLUSIONS: Gastric cancer detection was more frequent with implementation of a systematic surveillance protocol in CDH1 variant carriers. Given the decision for prophylactic surgery is often made by patients in the context of family history and pathologic result of surveillance biopsies, we propose the Bethesda protocol offers patients an opportunity to make more informed decisions.
    Keywords:  Cancer early detection; Endoscopy; Gastric cancer; Hereditary cancer syndromes
  7. J Med Genet. 2020 Nov 20. pii: jmedgenet-2020-107366. [Epub ahead of print]
    Moreno-Cabrera JM, Del Valle J, Feliubadaló L, Pineda M, González S, Campos O, Cuesta R, Brunet J, Serra E, Capellà G, Gel B, Lázaro C.
      INTRODUCTION: Germline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest.METHODS AND RESULTS: We evaluated a next-generation sequencing (NGS)-based CNV detection tool (DECoN) as first-tier screening to decrease costs and turnaround time and expand CNV analysis to all genes of clinical interest in our diagnostics routine. We used DECoN in a retrospective cohort of 1860 patients where a limited number of genes were previously analysed by MLPA, and in a prospective cohort of 2041 patients, without MLPA analysis. In the retrospective cohort, 6 new CNVs were identified and confirmed by MLPA. In the prospective cohort, 19 CNVs were identified and confirmed by MLPA, 8 of these would have been lost in our previous MLPA-restricted detection strategy. Also, the number of genes tested by MLPA across all samples decreased by 93.0% in the prospective cohort.
    CONCLUSION: Including an in silico germline NGS CNV detection tool improved our genetic diagnostics strategy in hereditary cancer, both increasing the number of CNVs detected and reducing turnaround time and costs.
    Keywords:  genetic testing; germ-line mutation; molecular diagnostic techniques
  8. Fam Cancer. 2020 Nov 20.
    Carwana H, Hoodfar E, Bergoffen J, Li D.
      Patients with mismatch repair (MMR) deficient colorectal cancer (CRC) without detectable germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) in MMR genes are often labeled as Lynch-like syndrome (LLS). We sought to evaluate the efficacy of paired tumor and germline testing in risk stratification of patients with LLS in a large, community-based, integrated healthcare setting. Through the universal screening program for Lynch syndrome at Kaiser Permanente Northern California, we identified all patients with MMR deficient colorectal tumors without detectable germline PVs or LPVs between April 2011 and October 2018. These patients were categorized as LLS and were offered paired tumor and germline testing. Risk stratification and patient management were assessed upon completion of all testing. Of the 50 patients with LLS who underwent paired tumor and germline testing, 62% (n = 31) were categorized as sporadic, 6% (n = 3) had Lynch syndrome, and 32% (n = 16) remained inconclusive. Among the sporadic cases, 65% (n = 20) had a PV (n = 18) or LPV (n = 2) in combination with loss of heterozygosity while 35% (n = 11) had two somatic PVs/LPVs involving the same MMR gene. Our findings showed paired tumor and germline testing resolved the etiology in the majority of patients and is a valuable strategy in risk stratification and management of patients with LLS. Further studies are needed to assess the optimal application of paired testing in different practice settings, particularly with evolving technology and decreasing cost of molecular sequencing.
    Keywords:  Colorectal cancer; Lynch syndrome; Lynch-like syndrome; Paired testing; Pathogenic variant; Somatic testing
  9. Annu Rev Med. 2020 Nov 20.
    Pilonis ND, Tischkowitz M, Fitzgerald RC, di Pietro M.
      Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene (CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see for revised estimates.
  10. Front Oncol. 2020 ;10 583314
    Huang X, Shao D, Wu H, Zhu C, Guo D, Zhou Y, Chen C, Lin Y, Lu T, Zhao B, Wang C, Sun Q.
      Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets. Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan-Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression. Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47-69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity. Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.
    Keywords:  BRCA1/2; CCNE1; genomic profiles; microsatellite instability; triple negative breast cancer; tumor mutation burden
  11. Clin Cancer Res. 2020 Nov 16. pii: clincanres.2892.2020. [Epub ahead of print]
    Latham A, Shia J, Patel Z, Reidy-Lagunes DL, Segal NH, Yaeger R, Ganesh K, Connell L, Kemeny NE, Kelsen DP, Hechtman JF, Nash GM, Paty PB, Zehir A, Tkachuk K, Sheikh R, Markowitz AJ, Mandelker D, Offit K, Berger MF, Cercek A, Garcia-Aguilar J, Saltz LB, Weiser MR, Stadler ZK.
      BACKGROUND: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBAs) in the setting of LS have not been well-studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.METHODS: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical (IHC) staining. Germline DNA was analyzed for mutations in known cancer-predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, EPCAM). Clinical variables were correlated with MMR/MSI status.
    RESULTS: 26% (26/100; 95% CI: 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). LS prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-LS MMR-D vs MMR-proficient (MMR-P) SBAs (65 vs 61, p= 0.75), but significantly younger in LS (47.5 vs 61; p=0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P vs 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in LS (p=0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared to 23.1% (6/26) in the MMR-D group (p=0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared to 18.2% (2/11) in the MMR-D group (p=0.0002).
    CONCLUSIONS: When compared to MMR-P SBA, MMR-D SBA is associated with earlier-stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline LS testing in MMR-D SBA is warranted.
  12. J Med Genet. 2020 Nov 20. pii: jmedgenet-2020-107102. [Epub ahead of print]
    Kim JH, Kim MJ, Kong SH, Kim SJ, Kang H, Shin CS, Park SS, Lee KE, Seong MW.
      BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing neuroendocrine tumours. PPGLs are a rare but important cause of secondary hypertension owing to their high morbidity and mortality. Patients with PPGL exhibit an increased prevalence of mutations in one of the PPGL susceptibility genes according to previous studies. We aimed to investigate the characteristics of germline mutations in the largest number of Korean patients with PPGL.METHODS: In this study, 161 patients with PPGL were evaluated. Phenotype data, including biochemical, pathological and anatomical imaging results, were collected. Germline mutations in 10 PPGL-related genes were tested by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification.
    RESULTS: Approximately 21% of apparently sporadic PPGLs harboured germline mutations of the PPGL-related genes. The mutation carriers were younger at the first diagnosis and had more bilateral (28.6% vs 4.0%, p<0.001) and multifocal (11.4% vs 1.6%, p=0.027) PPGLs, but showed no metastatic risk (17.1% vs 11.1%, p=0.504), than non-mutation carriers. Missense mutation of SDHD p.V111I was found in this cohort of Asian patients, which was associated with unilateral pheochromocytoma with dominantly epinephrine production.
    CONCLUSION: This study covered the largest number of Korean patients with PPGL. To our knowledge, it is the first to compare results of targeted NGS panel with those of conventional sequencing methods in Asia. We demonstrated that the variant type, as well as the mutated gene, may determine the phenotype and prognosis of PPGLs.
    Keywords:  endocrine gland neoplasms; genetic heterogeneity; genetic testing
  13. J Neurooncol. 2020 Nov 17.
    Poetsch L, Bronnimann C, Loiseau H, Frénel JS, Siegfried A, Seizeur R, Gauchotte G, Cappellen D, Carpentier C, Figarella-Branger D, Eimer S, Meyronet D, Ducray F, .
      BACKGROUND: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations).OBJECTIVE: The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas.
    MATERIALS AND METHODS: We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas.
    RESULTS: The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas.
    CONCLUSION: Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.
    Keywords:  Infra-tentorial gliomas; Inherited predisposition to cancer; Multicentric gliomas; Non-canonical IDH mutant gliomas
  14. Am J Transl Res. 2020 ;12(10): 6965-6972
    Zheng Y, Zhang H, Lu Q, Chu X, Gao L, Xiao P, Pan J, Hu S.
      CCAAT-enhancer-binding protein α (CEBPA) gene carrying two mutations (CEBPA double mutations) is known to promote familial acute myeloid leukemia (AML). However, the underlying mechanism by which CEBPA double mutations promote AML remains poorly understood. Here we report that a family with three generations suffering from familial AML carries novel double mutations of CEBPA. Seven bases of GCGCGGG were inserted into the N-terminal c.113-114 of CEBPA as germline mutations and three bases of AAG were inserted into the C-terminal c.939-940 as a somatic mutation. To test the functional impact of this double mutation, we constructed plasmid encoding the double mutants of CEBPA and transfected it into the myeloid precursor 32Dcl3 cells. Lentiviral induced overexpression of CEBPA with these double mutations inhibited myeloid differentiation of these 32Dcl3 cells, and led to approximately 4-fold fewer frequency of CD11b expression. Our results confirm that the double mutations of CEBPA at both N- and C-terminals are potentially to induce leukemogenesis of AML.
    Keywords:  CEBPA mutation; familial AML; germline mutation
  15. Front Oncol. 2020 ;10 553080
    Pouptsis A, Swafe L, Patwardhan M, Stavraka C.
      Hereditary breast cancer accounts for 5%-10% of breast cancer cases. The majority of familial cases have been linked to germline mutations in BRCA1 and BRCA2 genes, though other high penetrance susceptibility genes have also been identified through genomic testing advances. Optimal surgical treatment for these patients, who are of a younger age, has several challenges as it usually involves aggressive therapeutic and risk reducing interventions. At the same time, the therapeutic armamentarium for BRCA1/2 mutation carriers apart from platinum salts, has been enriched with the addition of poly-ADP ribose polymerase (PARP) inhibitors with promising outcomes. In this review we provide a succinct and comprehensive overview of the surgical and systemic treatment options for patients with BRCA1/2 mutation related breast cancer and an update on the most recent systemic treatment advances.
    Keywords:  BRCA1; BRCA2; breast cancer; genes; hereditary; surgical management; systemic treatment
  16. Front Oncol. 2020 ;10 564694
    Tang T, Wang LA, Wang P, Tong D, Liu G, Zhang J, Dai N, Zhang Y, Yuan G, Geary K, Zhang D, Liu Q, Jiang J.
      Background: Mutation-caused loss-of-function of factors involved in DNA damage response (DDR) is responsible for the development and progression of ~20% of prostate cancer (PCa). Some mutations can be used in cancer risk assessment and informed treatment decisions.Methods: Target capture-based deep sequencing of 11 genes was conducted with total DNA purified from the proband's peripheral blood. Sanger sequencing was conducted to screen potential germline mutations in the proband's family members. Targeted sequencing of a panel of 1,021 genes was done with DNA purified from the tumor tissue.
    Results: Two previously unreported germline mutations in the DDR pathway, BRCA2 (c.8474_8487delCATACCCTATACAG, p.A2825Vfs*15) and PALB2 (c.472delC, p.Q158Rfs*19) were identified in a patient with metastatic PCa. A specific therapeutic regimen including androgen deprivation therapy, locally radical radiotherapy, and systemic platinum chemotherapy worked well against his cancer. In addition, the metastatic ovarian cancer in the proband's half-sister harboring the same BRCA2 germline mutation also responded well to platinum chemotherapy.
    Conclusions: The newly identified germline mutations in DDR plays important role in PCa development. Since specific regimen worked well against this cancer, screening of DDR mutation could provide better management for patients with these mutation-mediated PCa.
    Keywords:  BRCA2; PALB2; case report; platinum-based chemotherapy; prostate cancer; radiotherapy
  17. JAAPA. 2020 Nov 06.
    Brown GR, Simon M, Wentling C, Spencer DM, Parker AN, Rogers CA.
      Inherited cancer syndromes are caused by genetic mutations that place patients at an increased risk for developing cancer. Although most cancers are not caused by genetic inheritance, clinicians must understand these syndromes and be able to recognize their common characteristics. A thorough family history and identification of common patterns as well as specific clinical signs and symptoms can help with early recognition. This article describes symptoms of the more common cancer syndromes, including hereditary breast and ovarian cancer, Li-Fraumeni, Lynch, familial adenomatous polyposis, retinoblastoma, multiple endocrine neoplasia, and von Hippel-Lindau. Important patient education regarding genetic testing also is covered.
  18. Front Genet. 2020 ;11 829
    Hu ZY, Liu L, Xie N, Lu J, Liu Z, Tang Y, Wang Y, Yang J, Ouyang Q.
      PALB2 is an important BRCAx candidate for familial breast cancers (FBC). PALB2 pathogenic variants (PVs) may not to conform to "two hit" paradigm. However, a recent study demonstrates that in the majority PALB2 germline mutant breast cancers, the loss of heterozygosity (LOH) and somatic point mutations are the "second hit." This study aimed to investigate the second hits in germline PALB2 mutations in breast cancers. We screened out 28 germline PALB2-mutation carriers among 480 familial cancer patients (including 143 FBC patients) in Geneplus database pool. Of the 143 patients with FBC, 10 had mono-allelic PALB2 germline mutations. All these germline PALB2 mutations were high-risk stop-gain, frameshift, or splicing mutations that concentrated in EX5-EX9 and might led to truncated proteins, severe functional defects and malignant phenotype. The hotspots were c.1057A[3 > 2] and c.3114-1G > A. Other mutations included c.389delA, c.2068C > T, c.2167_2168delAT, c.2629delT and c.2968G > T. Only one FBC patient has PALB2 somatic mutation and two patients had LOH of PALB2. All germline PALB2 mutations were high-risk mutations, whereas the somatic PALB2 mutations were moderate-risk missense mutations. We also distinguished PALB2 "novel mutations" from "reported mutations." In conclusion, germline PALB2 mutation should be put into the context of future screening.
    Keywords:  germline PALB2 mutation; hereditary breast cancer; loss of heterozygosity; mutational signature; somatic mutations
  19. Cancers (Basel). 2020 Nov 18. pii: E3419. [Epub ahead of print]12(11):
    Dueñas N, Navarro M, Teulé À, Solanes A, Salinas M, Iglesias S, Munté E, Ponce J, Guardiola J, Kreisler E, Carballas E, Cuadrado M, Matias-Guiu X, de la Ossa N, Lop J, Lázaro C, Capellá G, Pineda M, Brunet J.
      BACKGROUND: Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals.METHODS: Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort.
    RESULTS: Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (p = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% (p = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC (p = 0.001) and 0% vs. 12.7% for OC (p N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% (p N/A), for RRGS vs. surveillance, respectively.
    CONCLUSIONS: RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.
    Keywords:  Lynch syndrome; colorectal neoplasms; endometrial neoplasms; gynecological neoplasms; ovarian neoplasms; prophylactic surgical procedures; risk reducing surgery; risk reduction
  20. Fam Cancer. 2020 Nov 19.
    Gensini F, Sestini R, De Luca A, Pinna V, Daniele P, Orzalesi L, Petrella MC, Porfirio B, Papi L.
      We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes. Therefore, tumor analyses helped to establish that the germline NF1 and BRCA1 variants were in cis on the paternal chromosome. This last information is important to provide adequate genetic counselling regarding the risk of recurrence in the offspring, as well as opportunity for early intervention. In conclusion, we present the first case of a malignant phyllodes tumor of the breast in patient carrying pathogenic variants in NF1 and BRCA1. Further studies will be necessary to understand if the phyllodes histotype represents a very rare component of NF1-associated breast cancer.
    Keywords:  BRCA1; Breast cancer.; Malignant phyllodes tumor; NF1; Neurofibromatosis type 1
  21. Front Oncol. 2020 ;10 566822
    Carta R, Del Baldo G, Miele E, Po A, Besharat ZM, Nazio F, Colafati GS, Piccirilli E, Agolini E, Rinelli M, Lodi M, Cacchione A, Carai A, Boccuto L, Ferretti E, Locatelli F, Mastronuzzi A.
      Medulloblastoma is the most common malignant brain tumor in children. In addition to sporadic cases, medulloblastoma may occur in association with cancer predisposition syndromes. This review aims to provide a complete description of inherited cancer syndromes associated with medulloblastoma. We examine their epidemiological, clinical, genetic, and diagnostic features and therapeutic approaches, including their correlation with medulloblastoma. Furthermore, according to the most recent molecular advances, we describe the association between the various molecular subgroups of medulloblastoma and each cancer predisposition syndrome. Knowledge of the aforementioned conditions can guide pediatric oncologists in performing adequate cancer surveillance. This will allow clinicians to promptly diagnose and treat medulloblastoma in syndromic children, forming a team with all specialists necessary for the correct management of the other various manifestations/symptoms related to the inherited cancer syndromes.
    Keywords:  cancer genes; cancer predisposition; cancer syndromes; hereditary neoplastic syndromes; medulloblastoma; pediatric brain tumors
  22. Front Pediatr. 2020 ;8 570084
    Sharma R, Lewis S, Wlodarski MW.
      DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function mutations in DNA damage repair genes. DNA repair syndromes with biallelic disturbance of essential DNA damage response pathways manifest early in life with multi-systemic involvement and a high propensity for hematologic and solid cancers, as well as bone marrow failure. In this review, we describe classic biallelic DNA repair cancer syndromes arising from faulty single- and double-strand DNA break repair, as well as dysfunctional DNA helicases. These clinical entities include xeroderma pigmentosum, constitutional mismatch repair deficiency, ataxia telangiectasia, Nijmegen breakage syndrome, deficiencies of DNA ligase IV, NHEJ/Cernunnos, and ERCC6L2, as well as Bloom, Werner, and Rothmund-Thompson syndromes. To give an in-depth understanding of these disorders, we provide historical overview and discuss the interplay between complex biology and heterogeneous clinical manifestations.
    Keywords:  DNA repair; cancer predisposition; hematological malignances; hereditary cancer; pediatric cancer
  23. Cancer Genet. 2020 Nov 06. pii: S2210-7762(20)30280-5. [Epub ahead of print]250-251 6-11
    Nogueira CS, Silva-Fernandes IJL, de Albuquerque CGP, Oliveira FFB, Wong DVT, Silva PGB, Bitencourt FDS, Lima MVA.
      INTRODUCTION: Identifying carriers of genetic mutations that increase the risk of developing cancer allows to adopt timely risk-reducing strategies. However, due to the elevated cost of genetic testing, few oncogenetics services are available in the Brazilian public health care system, especially in economically disadvantaged areas.OBJECTIVE: To describe the implementation of an oncogenetics service for patients suspected of hereditary cancer syndromes (HBOC and HNPCC) at a philanthropic referral oncology hospital in Northeastern Brazil, funded by the Ministry of Health's National Oncology Care Support Program (PRONON).
    METHODS: The service was implemented with the PDCA method (Plan, Do, Check and Act).
    RESULTS: During the first year of operation (starting in August 2018), 675 individuals were examined, of whom 272 patients and 98 family members were submitted to genetic testing. This included the collection of 338 DNA samples of which 300 were sequenced. The analysis identified 48 (17.1%) mutations for HBOC and 19 (6.8%) for HNPCC.
    CONCLUSION: In one year, the oncogenetics service was able to benefit over 300 families by generating advanced molecular data which may be used for tailoring cancer prevention and management.
    Keywords:  Breast neoplasms; Colorectal neoplasms; Lynch syndrome; Mutagenicity testing; Ovarian neoplasms
  24. Trends Genet. 2020 Nov 14. pii: S0168-9525(20)30294-8. [Epub ahead of print]
    Chatrath A, Ratan A, Dutta A.
      Germline variants have a rich history of being studied in the context of cancer risk. Emerging studies now suggest that germline variants contribute not only to cancer risk but to tumor progression as well. In this opinion article, we discuss the initial discoveries associating germline variants with patient outcome and the mechanisms by which germline variants affect molecular pathways. Germline variants affect molecular pathways through amino acid changes, alteration of splicing patterns or expression of genes, influencing the selection for somatic mutations, and causing genome-wide mutational enrichment. These molecular alterations can lead to tumor phenotypes that become clinically apparent such as metastasis, alterations to the immune microenvironment, and modulation of therapeutic response. Overall, the growing body of evidence suggests that germline variants play a larger role in tumor progression than has been previously appreciated and that germline variation holds substantial potential for improving personalized medicine and patient outcomes.
    Keywords:  cancer therapy; germline variants; personalized medicine; tumor progression
  25. Rev Esp Enferm Dig. 2020 Nov 20.
    Zhou J, Liang C, Qing D, Wang Y, Tan Y, Shi X.
      Gardner syndrome is a hereditary disease characterized by familial adenomatous polyposis(FAP) accompanying with soft tissue tumors. A Chinese FAP family was enrolled and supervised for 3 years. A novel large germline fragment deletion(EX10_16DEL) of adenomatous polyposis coli(APC) gene was identified by multiplex ligation-dependent probe amplification (MLPA). An unexpected abdominal tumor grew 2 years after subtotal colectomy of the proband. The immunohistochemistry of abdominal tumor showed SMA(focal+), Calponin(+), β-catenin(nucleus+), CD34(focal+), CD117(-), which conformed to desmoid. When FAP related desmoid tumor occurred, the possibility of Gardner syndrome should be considered. This is the first largest deletion of the APC gene in the Chinese population associated with Gardner syndrome.
  26. Clin J Oncol Nurs. 2020 Dec 01. 24(6): 623-626
    Mahon SM.
      Tumor genomic testing is used primarily to facilitate the selection of the best possible treatment for a malignancy based on the genomic characteristics of the tumor. Germline genomic testing has implications for care and recommendations for cancer prevention and early detection for the patient and their family. Careful review of specific components of tumor genomic testing reports and of the family history of malignancy can help ensure that families with potential germline risk are identified and referred for genetic counseling and genetic testing.
    Keywords:  germline genomic testing; malignancy; tumor genomic testing; variant
  27. Sci Rep. 2020 Nov 19. 10(1): 20222
    Zhao S, Agafonov O, Azab A, Stokowy T, Hovig E.
      Advances in next-generation sequencing technology have enabled whole genome sequencing (WGS) to be widely used for identification of causal variants in a spectrum of genetic-related disorders, and provided new insight into how genetic polymorphisms affect disease phenotypes. The development of different bioinformatics pipelines has continuously improved the variant analysis of WGS data. However, there is a necessity for a systematic performance comparison of these pipelines to provide guidance on the application of WGS-based scientific and clinical genomics. In this study, we evaluated the performance of three variant calling pipelines (GATK, DRAGEN and DeepVariant) using the Genome in a Bottle Consortium, "synthetic-diploid" and simulated WGS datasets. DRAGEN and DeepVariant show better accuracy in SNP and indel calling, with no significant differences in their F1-score. DRAGEN platform offers accuracy, flexibility and a highly-efficient execution speed, and therefore superior performance in the analysis of WGS data on a large scale. The combination of DRAGEN and DeepVariant also suggests a good balance of accuracy and efficiency as an alternative solution for germline variant detection in further applications. Our results facilitate the standardization of benchmarking analysis of bioinformatics pipelines for reliable variant detection, which is critical in genetics-based medical research and clinical applications.
  28. Front Oncol. 2020 ;10 590033
    Capasso M, Montella A, Tirelli M, Maiorino T, Cantalupo S, Iolascon A.
      Progresses over the past years have extensively improved our capacity to use genome-scale analyses-including high-density genotyping and exome and genome sequencing-to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.
    Keywords:  SNP; cancer predisposition genes; cancer susceptibility; genetic predisposition; germline variants; germline-somatic interaction; next generation sequencing; pediatric tumors
  29. J Endocr Soc. 2020 Dec 01. 4(12): bvaa071
    De Sousa SMC, Toubia J, Hardy TSE, Feng J, Wang P, Schreiber AW, Geoghegan J, Hall R, Rawlings L, Buckland M, Luxford C, Novos T, Clifton-Bligh RJ, Poplawski NK, Scott HS, Torpy DJ.
      Context: Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2-collectively, "SDHx") have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline SDHx mutation.Methods: We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA.
    Results: Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect.
    Conclusions: This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.
    Keywords:  SDHC; intronic mutation; paraganglioma; succinate dehydrogenase; whole-exome sequencing
  30. JAMA. 2020 Nov 17. 324(19): 1957-1969
    AlDubayan SH, Conway JR, Camp SY, Witkowski L, Kofman E, Reardon B, Han S, Moore N, Elmarakeby H, Salari K, Choudhry H, Al-Rubaish AM, Al-Sulaiman AA, Al-Ali AK, Taylor-Weiner A, Van Allen EM.
      Importance: Less than 10% of patients with cancer have detectable pathogenic germline alterations, which may be partially due to incomplete pathogenic variant detection.Objective: To evaluate if deep learning approaches identify more germline pathogenic variants in patients with cancer.
    Design, Setting, and Participants: A cross-sectional study of a standard germline detection method and a deep learning method in 2 convenience cohorts with prostate cancer and melanoma enrolled in the US and Europe between 2010 and 2017. The final date of clinical data collection was December 2017.
    Exposures: Germline variant detection using standard or deep learning methods.
    Main Outcomes and Measures: The primary outcomes included pathogenic variant detection performance in 118 cancer-predisposition genes estimated as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The secondary outcomes were pathogenic variant detection performance in 59 genes deemed actionable by the American College of Medical Genetics and Genomics (ACMG) and 5197 clinically relevant mendelian genes. True sensitivity and true specificity could not be calculated due to lack of a criterion reference standard, but were estimated as the proportion of true-positive variants and true-negative variants, respectively, identified by each method in a reference variant set that consisted of all variants judged to be valid from either approach.
    Results: The prostate cancer cohort included 1072 men (mean [SD] age at diagnosis, 63.7 [7.9] years; 857 [79.9%] with European ancestry) and the melanoma cohort included 1295 patients (mean [SD] age at diagnosis, 59.8 [15.6] years; 488 [37.7%] women; 1060 [81.9%] with European ancestry). The deep learning method identified more patients with pathogenic variants in cancer-predisposition genes than the standard method (prostate cancer: 198 vs 182; melanoma: 93 vs 74); sensitivity (prostate cancer: 94.7% vs 87.1% [difference, 7.6%; 95% CI, 2.2% to 13.1%]; melanoma: 74.4% vs 59.2% [difference, 15.2%; 95% CI, 3.7% to 26.7%]), specificity (prostate cancer: 64.0% vs 36.0% [difference, 28.0%; 95% CI, 1.4% to 54.6%]; melanoma: 63.4% vs 36.6% [difference, 26.8%; 95% CI, 17.6% to 35.9%]), PPV (prostate cancer: 95.7% vs 91.9% [difference, 3.8%; 95% CI, -1.0% to 8.4%]; melanoma: 54.4% vs 35.4% [difference, 19.0%; 95% CI, 9.1% to 28.9%]), and NPV (prostate cancer: 59.3% vs 25.0% [difference, 34.3%; 95% CI, 10.9% to 57.6%]; melanoma: 80.8% vs 60.5% [difference, 20.3%; 95% CI, 10.0% to 30.7%]). For the ACMG genes, the sensitivity of the 2 methods was not significantly different in the prostate cancer cohort (94.9% vs 90.6% [difference, 4.3%; 95% CI, -2.3% to 10.9%]), but the deep learning method had a higher sensitivity in the melanoma cohort (71.6% vs 53.7% [difference, 17.9%; 95% CI, 1.82% to 34.0%]). The deep learning method had higher sensitivity in the mendelian genes (prostate cancer: 99.7% vs 95.1% [difference, 4.6%; 95% CI, 3.0% to 6.3%]; melanoma: 91.7% vs 86.2% [difference, 5.5%; 95% CI, 2.2% to 8.8%]).
    Conclusions and Relevance: Among a convenience sample of 2 independent cohorts of patients with prostate cancer and melanoma, germline genetic testing using deep learning, compared with the current standard genetic testing method, was associated with higher sensitivity and specificity for detection of pathogenic variants. Further research is needed to understand the relevance of these findings with regard to clinical outcomes.
  31. Transl Androl Urol. 2020 Oct;9(5): 2331-2347
    Gillespie NJ, Van Mater D.
      Several hereditary cancer predisposition syndromes are associated with genitourinary (GU) manifestations in children. The GU manifestation may be the first symptom of a more global syndrome to arise, which places the pediatric urologist in a unique position to impact the health of the child. Some GU manifestations are pathognomonic for a particular hereditary cancer predisposition syndrome, which can prompt genetic testing and enhanced surveillance for other features of the condition. In other cases, knowledge of an underlying hereditary cancer predisposition syndrome alters treatment decisions. This review focuses on hereditary cancer predisposition syndromes that impact the GU tract and are likely to be seen by a pediatric urologist.
    Keywords:  Cancer predisposition syndrome; DICER1; Wilms tumor; children; pediatric; von Hippel-Lindau
  32. Clin Cancer Res. 2020 Nov 16. pii: clincanres.3322.2020. [Epub ahead of print]
    Topka S, Steinsnyder Z, Ravichandran V, Tkachuk K, Kemel Y, Bandlamudi C, Winkel Madsen M, Furberg H, Ouerfelli O, Rudin CM, Iyer G, Lipkin SM, Mukherjee S, Solit DB, Berger MF, Bajorin DF, Rosenberg JE, Taylor BS, de Stanchina E, Vijai J, Offit K.
      PURPOSE: Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explore the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities.EXPERIMENTAL DESIGN: We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wildtype and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs.
    RESULTS: We found that putative damaging germline and somatic alterations in NER genes are present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard of care agent, cisplatin. Hypomorphic ERCC2/3 mutant cells have impaired ability to repair irofulven induced DNA damage. Transcriptomic profiling of tumor tissues suggested co-dependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies.
    CONCLUSIONS: These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs.
  33. Front Oncol. 2020 ;10 593383
    Monti P, Menichini P, Speciale A, Cutrona G, Fais F, Taiana E, Neri A, Bomben R, Gentile M, Gattei V, Ferrarini M, Morabito F, Fronza G.
      The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as a tetrameric transcription factor capable of regulating the expression of a plethora of target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. TP53 is the most commonly mutated gene in human cancer cells and TP53 germ-line mutations are responsible for the cancer-prone Li-Fraumeni syndrome. When mutated, the TP53 gene generally presents missense mutations, which can be distributed throughout the coding sequence, although they are found most frequently in the central DNA binding domain of the protein. TP53 mutations represent an important prognostic and predictive marker in cancer. The presence of a TP53 mutation does not necessarily imply a complete P53 inactivation; in fact, mutant P53 proteins are classified based on the effects on P53 protein function. Different models have been used to explore these never-ending facets of TP53 mutations, generating abundant experimental data on their functional impact. Here, we briefly review the studies analysing the consequences of TP53 mutations on P53 protein function and their possible implications for clinical outcome. The focus shall be on Chronic Lymphocytic Leukemia (CLL), which also has generated considerable discussion on the role of TP53 mutations for therapy decisions.
    Keywords:  P53 protein function; TP53 mutations; chronic lymphocytic leukemia; clinical impact; reactivation of P53
  34. Am J Med Genet A. 2020 Dec;182(12): 2813-2814
  35. Endocrinol Diabetes Nutr. 2020 Nov 12. pii: S2530-0164(20)30216-0. [Epub ahead of print]
    Orois A, Mora M, Halperin I, Oriola J.
      Familial non-medullary thyroid cancer is defined as the presence of non-medullary thyroid cancer in two or more first-degree relatives, in the absence of other predisposing factors. It represents up to 9% of differentiated thyroid cancers, and only a minority appears in well-known hereditary syndromes that associate thyroid cancer among many other clinical manifestations. However, in more than 95% of cases, thyroid cancer appears isolated, and its genetic causes have yet to be elucidated. We review here the current knowledge of the genetic basis of this pathology, as well as its clinical characteristics. Understanding the genetic mechanisms implied would help to comprehend the metabolic pathways involved, with the consequent potential therapeutic application. In addition, it would allow genetic counseling and to focus our efforts on patients at risk of developing this disorder.
    Keywords:  Cáncer de tiroides; Familial; Familiar; Genetics; Genética; Germline mutations; Mutaciones germinales; No medular; Non-medullary; Thyroid cancer
  36. J Med Genet. 2020 Nov 18. pii: jmedgenet-2020-107385. [Epub ahead of print]
    Pontén E, Frisk S, Taylan F, Vaz R, Wessman S, de Kock L, Pal N, Foulkes WD, Lagerstedt-Robinson K, Nordgren A.
      BACKGROUND: Germline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.METHODS: Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.
    RESULTS: A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.
    CONCLUSION: The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome ('DICER1 syndrome plus'), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
    Keywords:  genetic predisposition to disease; genetics; genomics; medical
  37. Front Pediatr. 2020 ;8 568528
    Chiang J, Yuen J, Shaw T, Goh HX, Li ST, Courtney E, Ngeow J.
      Approximately 10% of pediatric cancer patients possess germline pathogenic/likely pathogenic variants (PV/LPV) in known tumor predisposition genes. Predictive testing is the optimal approach to identify asymptomatic at-risk relatives to guide gene-directed surveillance for early cancer detection and/or risk-reducing strategies. However, the uptake rate for predictive testing remains low in Asian countries. We aim to evaluate the uptake rate of predictive testing in a pediatric population (aged under 21-years-old) in a multi-ethnic Asian cancer center. Our retrospective analysis included families with PV/LPVs identified in genes associated with pediatric tumor predisposition. Of the 83 pediatric first-degree relatives (FDRs) from 49 unrelated families, 20 FDRs (24.1%) originating from 13 families (26.6%) underwent predictive testing. Genes tested in pediatric FDRs were APC, RB1, SBDS, SDHA, SDHB, SDHD, and TP53. All pediatric FDRs of probands with PV/LPVs in RB1 and biallelic PVs in SBDS underwent predictive testing, while <45% of pediatric FDRs had predictive testing for familial PV/LPVs identified in the APC, SDHA, SDHB, SDHD, and TP53 genes. Amongst the 13 families who underwent pre-test counseling, 80% of pediatric FDRs in these families proceeded with predictive testing. Malay pediatric FDRs and siblings of probands were more likely to undergo predictive testing. We conclude that the predictive testing rate in pediatric FDRs is higher than that of adult FDRs in Asia, but still below the global average. We postulate factors that may influence predictive testing uptake in pediatric FDRs includes a lack of genetics awareness, concerns regarding insurance, and genetic discrimination.
    Keywords:  Asia; cascade; hereditary cancer; pediatric; predictive testing
  38. Oncol Rep. 2020 Nov 11.
    Gong Y, Deng J, Wu X.
      Germline mutations are congenital genetic mutations in germ cells that originate from sperm or ovum and are generally incorporated into every cell of the offspring's body. Somatic mutations are acquired genetic mutations that form under the influence of environmental factors during embryo formation and epigenetic development. Generally, only a portion of the cells in the human body have the same somatic mutations. Clinical detection of germline mutations is intended to determine inherited malignancies and identify high‑risk families, and detection of somatic mutation is proposed to find targeted drugs, monitor tumor loading for guided therapy, and evaluate prognosis. Large‑scale population cohort studies have shown that germline mutations are closely related to the occurrence, development, and prognosis of diseases. Patients with cancer‑predisposition germline mutations can be used as sentinels in high‑risk families. Traditional histopathology is no longer enough to identify types of cancers. Even within a particular type of tumor, there is great heterogeneity between internal molecules. The Pan‑Cancer Research Program as well as other projects seek to use large quantities of data from different types of tumor research databases to carry out integrated analysis in order to establish potential non‑tumor‑specific tumor markers and targets by increasing the sample size to identify more molecular mechanisms. This review intends to summarize some of the relevant mechanisms underlying germline mutations in blood disorders.
  39. Pediatr Blood Cancer. 2020 Nov 19. e28804
    Farooki S, Olaiya O, Tarbell L, Clark NA, Linebarger JS, Stroh J, Ellis K, Lewing K.
      BACKGROUND: Pediatric palliative care (PPC) for oncology patients improves quality of life and the likelihood of goal-concordant care. However, barriers to involvement exist.OBJECTIVES: We aimed to increase days between PPC consult and death for patients with refractory cancer from a baseline median of 13.5 days to ≥30 days between March 2019 and March 2020.
    METHODS: Outcome measure was days from PPC consult to death; process measure was days from diagnosis to PPC consult. The project team surveyed oncologists to identify barriers. Plan-do-study-act cycles included establishing target diagnoses, offering education, standardizing documentation, and sending reminders.
    RESULTS: The 24-month baseline period included 30 patients who died and 25 newly diagnosed patients. The yearlong intervention period included six patients who died and 16 newly diagnosed patients. Interventions improved outcome and process measures. Targeted patients receiving PPC ≥30 days prior to death increased from 43% to 100%; median days from consult to death increased from 13.5 to 159.5. Targeted patients receiving PPC within 30 days of diagnosis increased from 28% to 63%; median days from diagnosis to consult decreased from 221.5 to 14. Of those without PPC consult ≤ 30 days after diagnosis, 17% had template documentation of the rationale.
    CONCLUSION: Interventions utilized met the global aim, outcome, and process measures. Use of QI methodology empowered providers to involve PPC. Poor template use was a barrier to identifying further drivers. Future directions for this project relate to expanding the target list, creating long-term sustainability, formalizing standards, and surveying patients and families.
    Keywords:  oncology; palliative care; pediatric palliative care; refractory cancer