bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021–01–10
eightteen papers selected by
Joanna Zawacka-Pankau, University of Warsaw
  1. Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome.
  2. Revisiting multiple erroneous genetic testing results and clinical misinterpretations in a patient with Li-Fraumeni syndrome: lessons for translational medicine.
  3. Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report.
  4. Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort.
  5. Metaplastic carcinoma of the breast and BRCA1 germline mutation: a case report and review.
  6. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
  7. Germline mutations in MDS/AML predisposition disorders.
  8. Clinical Implications of Germline Testing in Newly Diagnosed Prostate Cancer.
  9. Reliable assessment of BRCA1 and BRCA2 germline variants by next-generation sequencing: a multicenter study.
  10. BRCA1/2 pathogenic variants in triple-negative versus luminal-like breast cancers: genotype-phenotype correlation in a cohort of 531 patients.
  11. Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review.
  12. Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers.
  13. Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma.
  14. Cell Fate Decisions: The Role of Transcription Factors in Early B-cell Development and Leukemia.
  15. Prevalence of Germline Pathogenic and Likely Pathogenic Variants in Patients With Second Breast Cancers.
  16. Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer.
  17. Early-onset breast cancer in a woman with a germline mobile element insertion resulting in BRCA2 disruption: a case report.
  18. Functional Common and Rare ERBB2 Germline Variants Cooperate in Familial and Sporadic Cancer Susceptibility.
  1. Hered Cancer Clin Pract. 2021 Jan 06. 19(1): 1
    Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome.
    Ofelia Cruz, Victoria Caloretti, Hector Salvador, Veronica Celis, Vicente Santa-Maria, Andrés Morales La Madrid, Mariona Suñol, Patricia Puerta, Jordi Muchart, Lucas Krauel, Cinzia Lavarino.
       BACKGROUND: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome characterized by the early-onset of multiple primary cancers which can occur at different moments (metachronous onset) or, more rarely, coincidentally (synchronous onset). Here we describe a previously unreported patient with presentation of synchronous Wilms tumor and Choroid plexus papilloma, leading to the diagnosis of a Li-Fraumeni Syndrome (LFS).
    CASE PRESENTATION: A 6-year-old girl without previous complains presented with abdominal pain. Abdominal US and MRI showed a left renal tumor with subcapsular hematoma. Due to mild headaches, the diagnostic workup included a brain MRI that unexpectedly identified a large left parietal lobe tumor. Histopathological analysis determined the diagnosis of classic Wilms tumor and choroid-plexus papilloma (CPP), respectively. Both neoplasms showed intense nuclear p53 immunostaining associated with the pathogenic TP53 mutation c.844C > T (p.Arg282Trp). Our patient and her father shared the same heterozygous germline TP53 mutation, confirming the diagnosis of familiar Li-Fraumeni syndrome in the girl. The treatment was tailored to simultaneous tumor presentations.
    CONCLUSIONS: LFS has been associated with Choroid plexus carcinoma (CPC), but rarely with CPP as in our patient. That suggests that it may be advisable to consider the possibility of analyzing TP53 mutation, not only in all patients with CPC, but also in some patients with CPP, especially when histological or clinical evidences point out to perform this study. The dissimilar presentation of LFS among our patient's father, not having so far any neoplasia diagnosed, while her daughter presented precociously with two simultaneous different tumors, could be related to possible effects of modifier genes on the underlying mutant p53 genotype.
    Keywords:  Cancer predisposition syndrome; Choroid plexus papilloma; Choroidal plexus tumors; Li-Fraumeni syndrome; Synchronous neoplasia; TP53 mutation; Wilms tumor
    DOI:  https://doi.org/10.1186/s13053-020-00158-7
  2. Hered Cancer Clin Pract. 2021 Jan 06. 19(1): 2
    Revisiting multiple erroneous genetic testing results and clinical misinterpretations in a patient with Li-Fraumeni syndrome: lessons for translational medicine.
    Tatiana N Sokolova, Valeriy V Breder, Irina S Shumskaya, Evgeny N Suspitsin, Svetlana N Aleksakhina, Grigoriy A Yanus, Vladislav I Tiurin, Alexandr O Ivantsov, Barbara Vona, Grigoriy A Raskin, Sergey V Gamajunov, Evgeny N Imyanitov.
       BACKGROUND: Many cancer patients undergo sophisticated laboratory testing, which requires proper interpretation and interaction between different specialists.
    CASE PRESENTATION: We describe a patient with an extensive family history of cancer, who was diagnosed with bilateral breast cancer and two lung cancer lumps by the age of 40 years. She submitted a lung cancer specimen to a genetic profiling service, which reported the presence of the EGFR mutation (a combination of G719S and L833V substitutions) and the TP53 с.322_327del (p.G108_F109del) mutation in the tumor tissue. Possible therapeutic options were discussed at a medical conference, where one of the discussants raised a concern that the identified TP53 mutation may not necessarily be somatic, but reflect the germ-line status of the gene. Review of clinical records and follow-up dialog with the patient revealed, that she previously provided her blood for DNA analysis in two laboratories. The first laboratory utilized a custom NGS assay and did not detect the TP53 mutation, instead pointed to a potential pathogenic significance of the MSH6 c.2633 T > C (p.V878A) allele. The second laboratory revealed the TP53 с.322_327del (p.G108_F109del) allele but stated in the written report that it has an unknown pathogenic significance. To resolve the possible uncertainty regarding the role of the TP53 с.322_327del (p.G108_F109del) variant, we suggested that the patient invite her second cousin for genetic testing, as she was affected by neuroblastoma at the age of 3 years. This analysis revealed the presence of the same TP53 variant.
    CONCLUSION: We provide point-by-point discussion, reviewing multiple laboratory mistakes and clinical misinterpretations occurred with this patient. This case report exemplifies the need to involve rigorous clinical expertise in the daily practice of medical laboratory facilities.
    Keywords:  Breast cancer; Li-Fraumeni syndrome; Lung cancer; TP53
    DOI:  https://doi.org/10.1186/s13053-020-00157-8
  3. Hered Cancer Clin Pract. 2021 Jan 07. 19(1): 5
    Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report.
    Kodai Abe, Arisa Ueki, Yusaku Urakawa, Minoru Kitago, Tomoko Yoshihama, Yoshiko Nanki, Yuko Kitagawa, Daisuke Aoki, Kenjiro Kosaki, Akira Hirasawa.
       BACKGROUND: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis.
    CASE PRESENTATION: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary.
    CONCLUSIONS: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.
    Keywords:  Hereditary pancreatic cancer; NBN; PALB2
    DOI:  https://doi.org/10.1186/s13053-020-00160-z
  4. ESMO Open. 2021 Jan 04. pii: S2059-7029(20)32897-0. [Epub ahead of print]6(1): 100032
    Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort.
    U Peretti, A Cavaliere, M Niger, G Tortora, M C Di Marco, M G Rodriquenz, F Centonze, I G Rapposelli, G Giordano, F De Vita, L Stuppia, A Avallone, M Ratti, C Paratore, L G Forti, G Orsi, M M Valente, M Gaule, M Macchini, P Carrera, S Calzavara, M Simbolo, D Melisi, F De Braud, L Salvatore, S De Lorenzo, C Chiarazzo, M Falconi, S Cascinu, M Milella, M Reni.
       OBJECTIVE: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients.
    MATERIALS AND METHODS: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate.
    RESULTS: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations.
    CONCLUSION: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives.
    Keywords:  epidemiology; familial cancer; germline BRCA; pancreatic cancer genetics
    DOI:  https://doi.org/10.1016/j.esmoop.2020.100032
  5. Hered Cancer Clin Pract. 2021 Jan 06. 19(1): 3
    Metaplastic carcinoma of the breast and BRCA1 germline mutation: a case report and review.
    Michiko Yamashita, Yoshiaki Kamei, Akari Murakami, Erina Ozaki, Kumiko Okujima, Kana Takemoto, Megumi Takaoka, Daiki Tsukamoto, Erina Kusakabe, Tomoyuki Shidahara, Haruna Noda, Reina Aoki, Kana Taguchi, Kanako Nishiyama, Mariko Eguchi, Yasutsugu Takada.
       BACKGROUND: Metaplastic carcinoma of the breast consists of both invasive ductal carcinoma and metaplastic carcinoma. This rare subtype of cancer has a poor prognosis. The development of metaplastic breast cancer and relationship with BRCA1 are not well known. Here, we report a rare case of germline BRCA1 mutation-positive breast cancer with chondroid metaplasia.
    CASE PRESENTATION: A 39-year-old Japanese woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother consulted at our hospital with a left breast mass. Needle biopsy for the mass was performed, leading to a diagnosis of invasive breast cancer with chondroid metaplasia. We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion and replaced with a silicone implant later. Pathological examination revealed that the patient had triple-negative breast cancer. Four courses of doxorubicin+ cyclophosphamide therapy were performed as adjuvant therapy after surgery. We performed genetic counseling and genetic testing, and the results suggested the germline BRCA1 mutation 307 T> A (L63*). She has currently lived without a relapse for 2 years post-surgery.
    CONCLUSIONS: There have been only 6 cases of metaplastic breast carcinoma with germline BRCA1 mutations including our case. Patients with BRCA1 mutations may develop basal-like subtypes or M type of triple-negative breast cancer besides metaplastic breast cancers.
    Keywords:  BRCA1 mutation; Chondroid metaplasia; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s13053-020-00162-x
  6. J Natl Compr Canc Netw. 2021 Jan 06. pii: jnccnGLS1901. [Epub ahead of print]19(1): 77-102
    Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
    CGC
      The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
    DOI:  https://doi.org/10.6004/jnccn.2021.0001
  7. Curr Opin Hematol. 2020 Dec 24. Publish Ahead of Print
    Germline mutations in MDS/AML predisposition disorders.
    Lucy A Godley.
       PURPOSE OF REVIEW: Recognition of hereditary hematopoietic malignancies impacts patient management as well as health surveillance strategies for the patient and relatives who share the causative DNA variant. In this review, barriers to the diagnosis and management of patients are outlined.
    RECENT FINDINGS: Increasingly, individuals are being recognized as having germline predisposition to hematopoietic malignancies. Clinical testing for these syndromes is difficult for most clinicians given the need to send true germline samples and the lack of standardization in the field with regard to which genes are covered and the types of DNA changes detected. Additional barriers such as insurance coverage, especially for older individuals, and access to clinical experts need to be overcome in the future.
    SUMMARY: New research addressing whether use of hematopoietic stem cells with deleterious variants are permissive to transplantation; effective means of delivering genetic counseling and results disclosure to decrease the psychological impact of these diagnoses; and a comprehensive list of all predisposition genes will advance our ability to provide the best treatment possible for our patients and facilitate strategies to maintain excellent health throughout their lifetimes and for members of younger generations.
    VIDEO ABSTRACT: Submitted, http://links.lww.com/COH/A22.
    DOI:  https://doi.org/10.1097/MOH.0000000000000633
  8. Eur Urol Oncol. 2020 Dec 31. pii: S2588-9311(20)30207-8. [Epub ahead of print]
    Clinical Implications of Germline Testing in Newly Diagnosed Prostate Cancer.
    Stacy Loeb, Veda N Giri.
       CONTEXT: Germline testing (GT) is increasingly impacting prostate cancer (PCa) management and screening, with direct effects in urology, medical oncology, and radiation oncology. The majority of testing indications and recommendations center on men with metastatic disease, although guidelines now encompass newly diagnosed, early-stage PCa and entail assessment of personal history, pathologic features, and family history to determine eligibility for testing.
    OBJECTIVE: To describe current guidelines on GT for men with PCa and the impact on management. An additional objective was to review the literature on current uptake of GT across practice settings.
    EVIDENCE ACQUISITION: A nonsystematic review was performed of current guidelines on GT in PCa from professional societies and consensus conferences, detailing supporting evidence for these recommendations. This was supplemented by a literature review of uptake of GT and precision medicine in practice.
    EVIDENCE SYNTHESIS: Multiple guidelines and consensus panels recommend GT for men with metastatic PCa. Guidelines endorse BRCA2 testing in metastatic PCa because of strong evidence for PCa risk, aggressiveness, and PARP inhibitor candidacy. Testing of additional DNA repair genes in metastatic disease is also endorsed across guidelines. Immunotherapy with pembrolizumab is an option in some guidelines for men with DNA mismatch repair deficiency. In localized disease, GT is recommended on the basis of histologic features and family history; criteria vary between guidelines. GT for localized disease informs hereditary cancer risk and will probably impact future PCa management. Practice gaps exist regarding utilization of GT.
    CONCLUSIONS: Germline evaluation is increasingly important in the management of men with metastatic PCa and may also affect the prognosis for men with localized disease. The presence of germline mutations has important hereditary cancer implications for men and their families. Uptake of germline evaluation may be underutilized in some practice settings, so strategies for optimization are required.
    PATIENT SUMMARY: Patients with prostate cancer should talk to their doctor about the pros and cons of genetic testing, with attention to family history and cancer features. Genetic testing can have important implications for treatment, cancer screening, and family cancer risk.
    Keywords:  Genetic testing; Germline testing; Guidelines; Prostate cancer
    DOI:  https://doi.org/10.1016/j.euo.2020.11.011
  9. Breast Cancer. 2021 Jan 05.
    Reliable assessment of BRCA1 and BRCA2 germline variants by next-generation sequencing: a multicenter study.
    Rui Zhang, Peng Gao, Yanxi Han, Runling Zhang, Ping Tan, Li Zhou, Jiawei Zhang, Jiehong Xie, Jinming Li.
       BACKGROUND: BRCA1/2 gene mutation testing, based on next-generation sequencing (NGS), has been gradually applied in the clinic to serve as preventive early screening for predisposed individuals or to provide treatment options for patients with hereditary breast or ovarian cancers. Here, we evaluated the accuracy of NGS-based mutation detection in BRCA1/2 and the consistency in variant interpretation among clinical laboratories to find the possible reasons underlying inaccurate results and discrepant variant interpretation.
    METHODS: Laboratories were asked to use their routine procedures to detect six mimetic DNA samples with different BRCA1/2 germline variants. The results of variant detection were required to be submitted via a web-based evaluation system and were automatically scored, according to predefined criteria. The variant interpretation report, including the detailed clinical evidence, was summarized and analyzed for reasons underlying inconsistent results.
    RESULTS: Overall, only 55.2% (16/29) of laboratories, whose detection score was higher than 90 points, was found to be an acceptable detection capability level. 82.9% (29/35) of the errors were genotype errors. The variant classification results were generally consistent, and 77.8% (7/9) of the variants were given the consistent classification answer. Only two single nucleotide variants (SNVs) had a discrepant classification opinion across laboratories.
    CONCLUSIONS: The BRCA1/2 variant detection performance should be further improved, especially in reporting the correct genome coordinates. Inconsistent variant classification may be a result of the different clinical pieces of evidence collected by the laboratories. However, discordant clinical evidence also appeared within the same classification results. Therefore, our study provided clear clinical evidence assessment strategies for BRCA1/2 variants, which was aimed at obtaining a consistent variant classification strategy for providing accurate clinical reports to the clinicians.
    Keywords:  BRCA1/2; Germline variant; Next-generation sequencing; Variant interpretation
    DOI:  https://doi.org/10.1007/s12282-020-01204-x
  10. Ther Adv Med Oncol. 2020 ;12 1758835920975326
    BRCA1/2 pathogenic variants in triple-negative versus luminal-like breast cancers: genotype-phenotype correlation in a cohort of 531 patients.
    Lorena Incorvaia, Daniele Fanale, Marco Bono, Valentina Calò, Alessia Fiorino, Chiara Brando, Lidia Rita Corsini, Sofia Cutaia, Daniela Cancelliere, Alessia Pivetti, Clarissa Filorizzo, Maria La Mantia, Nadia Barraco, Stefania Cusenza, Giuseppe Badalamenti, Antonio Russo, Viviana Bazan.
       Background: Several available data suggest the association between specific molecular subtypes and BRCA1/2 mutational status. Previous investigations showed the association between BRCA1/2 pathogenic variants (PVs) in specific genomic regions and phenotypic variations of cancer relative risk, while the role of PV type and location in determining the breast cancer (BC) phenotypic features remains still unclear. The aim of this research was to describe the germline BRCA1/2 PVs in triple-negative breast cancer (TNBC) versus luminal-like BC and their potential leverage on BC phenotype.
    Patients & methods: We retrospectively collected and analyzed all clinical information of 531 patients with BC genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis at University Hospital Policlinico "P. Giaccone" of Palermo (Sicily) from January 2016 to February 2020.
    Results: Our results corroborate the evidence that BRCA1-related tumors often have a profile which resembles the TNBC subtype, whereas BRCA2-associated tumors have a profile that resembles luminal-like BC, especially the Luminal B subtype. Interestingly, our findings suggest that the PVs identified in TNBC were not largely overlapping with those in luminal-like tumors. Differences in the frequency of two PVs potentially associated with different molecular tumor subtypes were observed. BRCA1-633delC was detected with relatively higher prevalence in patients with TNBC, whereas BRCA2-1466delT was found mainly in Luminal B tumors, but in no TNBC patient.
    Conclusion: Future studies examining the type and location of BRCA1/2 PVs within different molecular subtypes are required to verify our hypothesis and could provide an interesting insight into the complex topic of genotype-phenotype correlations. Additionally, a more in-depth understanding of the potential correlations between BRCA PVs and clinical and phenotypic features of hereditary BC syndrome patients could be the key to develop better strategies of prevention and surveillance in BRCA-positive carriers without disease.
    Keywords:  BRCA1; BRCA2; breast cancer; genetic testing; germline pathogenic variants; luminal-like breast cancer; triple-negative breast cancer
    DOI:  https://doi.org/10.1177/1758835920975326
  11. JAMA Surg. 2021 Jan 06.
    Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review.
    Lauren A Gamble, Theo Heller, Jeremy L Davis.
       Importance: Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1.
    Observations: Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population.
    Conclusions and Relevance: The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.
    DOI:  https://doi.org/10.1001/jamasurg.2020.6155
  12. Gut. 2021 Jan 07. pii: gutjnl-2019-320462. [Epub ahead of print]
    Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers.
    Peter Georgeson, Bernard J Pope, Christophe Rosty, Mark Clendenning, Khalid Mahmood, Jihoon E Joo, Romy Walker, Ryan A Hutchinson, Susan Preston, Julia Como, Sharelle Joseland, Aung Ko Win, Finlay A Macrae, John L Hopper, Dmitri Mouradov, Peter Gibbs, Oliver M Sieber, Dylan E O'Sullivan, Darren R Brenner, Steve Gallinger, Mark A Jenkins, Ingrid M Winship, Daniel D Buchanan.
       OBJECTIVE: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.
    DESIGN: Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.
    RESULTS: The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.
    CONCLUSION: Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
    Keywords:  colorectal cancer; colorectal cancer screening; molecular pathology; mutations; tumour markers
    DOI:  https://doi.org/10.1136/gutjnl-2019-320462
  13. Endocrinol Metab (Seoul). 2020 Dec;35(4): 909-917
    Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma.
    Soo Hyun Seo, Jung Hee Kim, Man Jin Kim, Sung Im Cho, Su Jin Kim, Hyein Kang, Chan Soo Shin, Sung Sup Park, Kyu Eun Lee, Moon-Woo Seong.
       BACKGROUND: Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases. Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients. In this study, we used whole exome sequencing to identify novel causative variants associated with PPGL to improve the detection of rare genetic variants in our cohort.
    METHODS: Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing. Whole exome sequencing was performed using DNA samples enriched using TruSeq Custom Enrichment Kit and sequenced with MiSeq (Illumina Inc.). Sequencing alignment and variant calling were performed using SAMtools.
    RESULTS: Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes. SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma. Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.
    CONCLUSION: Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL. Implementation of targeted gene sequencing consisted of extended genes of PPGL in routine clinical screening can support the level of comprehensive patient assessment.
    Keywords:  Germ-line mutation; Molecular diagnostic techniques; Paraganglioma; Pheochromocytoma; Whole exome sequencing
    DOI:  https://doi.org/10.3803/EnM.2020.756
  14. Blood Cancer Discov. 2020 Nov;1(3): 224-233
    Cell Fate Decisions: The Role of Transcription Factors in Early B-cell Development and Leukemia.
    Ute Fischer, Jun J Yang, Tomokatsu Ikawa, Daniel Hein, Carolina Vicente-Dueñas, Arndt Borkhardt, Isidro Sánchez-García.
      B-cells are an integral part of the adaptive immune system and regulate innate immunity. Derived from hematopoietic stem cells they mature through a series of cell fate decisions. Complex transcriptional circuits form and dissipate dynamically during these lineage restrictions. Genomic aberrations of involved transcription factors underlie various B-cell disorders. Acquired somatic aberrations are associated with cancer, whereas germline variations predispose to both malignant and non-malignant diseases. We review the opposing role of transcription factors during B-cell development in health and disease. We focus on early B-cell leukemia and discuss novel causative gene-environment cooperations and their implications for precision medicine.
    Keywords:  B-cell; Transcription factors; childhood leukemia; environment; germline; mouse models; somatic
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0011
  15. JNCI Cancer Spectr. 2020 Dec;4(6): pkaa094
    Prevalence of Germline Pathogenic and Likely Pathogenic Variants in Patients With Second Breast Cancers.
    Katharine A Yao K, Jacob Clifford, Shuwei Li, Holly LaDuca, Peter Hulick, Stephanie Gutierrez, Mary Helen Black.
       Background: Few studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC).
    Methods: The frequency of pathogenic and likely pathogenic (P/LP) variants in clinically actionable genes (BRCA1, BRCA2, PTEN, TP53, CHEK2, CDH1, ATM, PALB2, NBN, and NF1) was compared between women with a primary breast cancer (PBC) and SBC who underwent multigene panel testing at a single diagnostic testing laboratory. Race- and ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes were used to test for associations with SBC. All statistical tests were 2-sided.
    Results: The study was comprised of 75 550 women with PBC and 7728 with SBC. Median time between breast cancers for SBC was 11 (interquartile range = 6-17) years. Restricting to women tested for all actionable genes (n = 60 310), there were 4231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared with 652 (11.1%) women with SBC (P< .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% confidence interval [CI] = 1.30 to 1.60) times as likely to have SBC than noncarriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (95% CI = 1.36 to 2.56) and 1.66 (9% CI = 1.02 to 2.58) times as likely to be associated with SBC, respectively (P < .001 and P = .03).
    Conclusion: Women with P/LP variants in breast cancer predisposition genes are more likely to have SBC than noncarriers. Prospective studies are needed confirm these findings.
    DOI:  https://doi.org/10.1093/jncics/pkaa094
  16. Cancers (Basel). 2021 Jan 01. pii: E118. [Epub ahead of print]13(1):
    Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer.
    Louisa Lepkes, Mohamad Kayali, Britta Blümcke, Jonas Weber, Malwina Suszynska, Sandra Schmidt, Julika Borde, Katarzyna Klonowska, Barbara Wappenschmidt, Jan Hauke, Piotr Kozlowski, Rita K Schmutzler, Eric Hahnen, Corinna Ernst.
      The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.
    Keywords:  CNV; HBOC; breast/ovarian cancer susceptibility genes; multigene panel sequencing
    DOI:  https://doi.org/10.3390/cancers13010118
  17. Hum Genome Var. 2020 Aug 25. 7(1): 24
    Early-onset breast cancer in a woman with a germline mobile element insertion resulting in BRCA2 disruption: a case report.
    Natalie Deuitch, Shao-Tzu Li, Eliza Courtney, Tarryn Shaw, Rebecca Dent, Veronique Tan, Lauren Yackowski, Rebecca Torene, Windy Berkofsky-Fessler, Joanne Ngeow.
      Mobile element insertions (MEIs) contribute to genomic diversity, but they can be responsible for human disease in some cases. Initial clinical testing (BRCA1, BRCA2 and PALB2) in a 40-year-old female with unilateral breast cancer did not detect any pathogenic variants. Subsequent reanalysis for MEIs detected a novel likely pathogenic insertion of the retrotransposon element (RE) c.7894_7895insSVA in BRCA2. This case highlights the importance of bioinformatic pipeline optimization for the detection of MEIs in genes associated with hereditary cancer, as early detection can significantly impact clinical management.
    DOI:  https://doi.org/10.1038/s41439-020-00111-z
  18. Cancer Prev Res (Phila). 2021 Jan 08. pii: canprevres.0094.2020. [Epub ahead of print]
    Functional Common and Rare ERBB2 Germline Variants Cooperate in Familial and Sporadic Cancer Susceptibility.
    Riyue Bao, Anita Ng, Mark Sasaki, Myvizhi Esai Selvan, Alyna Katti, Hyesan Lee, Lei Huang, Andrew D Skol, Cinzia Lavarino, Hector Salvador, Robert J Klein, Zeynep H Gümüş, Jaume Mora, Kenan Onel.
      We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in ERBB2/HER2 that is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (D'=1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk. Because multiple cancer types occurred in this family, we tested both the I654V and the I655V variants for association with cancer across multiple tumor types in 6,371 cases of Northern European ancestry drawn from The Cancer Genome Atlas and 6,647 controls, and found that the rare variant (I654V) was significantly associated with an increased risk for cancer (OR=1.40, p=0.021, 95% CI=1.05-1.89). Functional assays performed in HEK 293T cells revealed that both the I655V single mutant (SM) and the I654V;I655V double mutant (DM) stabilized ERBB2 protein and activated ERBB2 signaling, with the DM activating ERBB2 significantly more than the SM alone. Thus, our results suggest a model whereby heritable genetic variation in the transmembrane domain activating ERBB2 signaling is associated with both sporadic and familial cancer risk, with increased ERBB2 stabilization and activation associated with increased cancer risk.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-20-0094
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