bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒03‒22
fourteen papers selected by
Joanna Zawacka-Pankau

  1. J Thorac Oncol. 2020 Mar 13. pii: S1556-0864(20)30197-0. [Epub ahead of print]
    Mezquita L, Jove M, Nadal E, Kfoury M, Morán T, Ricordel C, Dhooge M, Tlemsani C, Léna H, Teulé A, Álvarez JV, Raimbourg J, Hiret S, Pharma LL, Menéndez M, Saldaña J, Brunet J, Lianes P, Coupier I, Auclin E, Recondo G, Friboulet L, Adam J, Green E, Planchard D, Frébourg T, Capellà G, Rouleau E, Lázaro C, Caron O, Besse B.
      BACKGROUND: Actionable somatic molecular alterations are found in 15 to 20% of non-small cell lung cancer (NSCLC) in the Caucasians. NSCLC is a tumor observed in patients with germline-<I>TP53 </I>variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown.METHODS: Retrospective study of clinical and molecular profile of NSCLC in patients with germline-TP53 variants.
    RESULTS: In 22 NSCLC patients with LFS (n=23 lung tumors), 64% were female, median age 51, 74% non-smokers, 73% with adenocarcinoma histology and 84% were diagnosed with advanced stage disease. These 22 patients harbor 16 distinct germline TP53 variants; the most common was p.R158H (5/22; 3 in the same family). Personal and familiar history of cancer was reported in 71% and 90% of patients, respectively. Lung cancer was in most of the cases (87%, 13/15) a late-onset diagnosis. Among the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19/21 (90%), 18 EGFR-mutations (exon-19 deletions in 12 cases, L858R in 3 cases and G719A, exon-20 insertion, missing mutation subtype, each in one case) and one case with ROS1 fusion. A PI3KCA mutation was concurrently detected at diagnosis in 3 EGFR exon 19 deletion tumors (3/12). The median OS was 37.3 months in 14 patients treated with EGFR-inhibitors; 7 developed resistance, 5 (71%) with acquired EGFR-T790M mutation and one with SCLC transformation.
    CONCLUSION: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations but also one ROS1 fusion. The germline-TP53 variants and lung cancer carcinogenesis driven by oncogenic processes needs further evaluation.
  2. JAMA Oncol. 2020 Mar 19.
    Mirabello L, Zhu B, Koster R, Karlins E, Dean M, Yeager M, Gianferante M, Spector LG, Morton LM, Karyadi D, Robison LL, Armstrong GT, Bhatia S, Song L, Pankratz N, Pinheiro M, Gastier-Foster JM, Gorlick R, de Toledo SRC, Petrilli AS, Patino-Garcia A, Lecanda F, Gutierrez-Jimeno M, Serra M, Hattinger C, Picci P, Scotlandi K, Flanagan AM, Tirabosco R, Amary MF, Kurucu N, Ilhan IE, Ballinger ML, Thomas DM, Barkauskas DA, Mejia-Baltodano G, Valverde P, Hicks BD, Zhu B, Wang M, Hutchinson AA, Tucker M, Sampson J, Landi MT, Freedman ND, Gapstur S, Carter B, Hoover RN, Chanock SJ, Savage SA.
      Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma.
    Design, Setting, and Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.
    Main Outcomes and Measures: The frequency of rare pathogenic or likely pathogenic genetic variants.
    Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53.
    Conclusions and Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
  3. Gastroenterology. 2020 Mar 13. pii: S0016-5085(20)30336-X. [Epub ahead of print]
    Bonjoch L, Franch-Expósito S, Garre P, Belhadj S, Muñoz J, Arnau-Collell C, Díaz-Gay M, Gratacós-Mulleras A, Raimondi G, Esteban-Jurado C, Soares de Lima Y, Herrera-Pariente C, Cuatrecasas M, Ocaña T, Castells A, Fillat C, Capellá G, Balaguer F, Caldés T, Valle L, Castellví-Bel S.
      BACKGROUND & AIMS: A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC.METHODS: We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time PCR, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or NF-κB activity.
    RESULTS: We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate b-catenin in the cytoplasm, and translocate NF-kB to the nucleus.
    CONCLUSIONS: In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of b-catenin and NF-kB.
    Keywords:  Wnt signaling; functional genomics; gene editing; programmed cell death
  4. J Cutan Pathol. 2020 Mar 18.
    Cloutier JM, Shalin SC, Lindberg M, Gardner JM, Fernandez-Pol S, Zaba L, Novoa R, Brown RA.
      Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (≤2 cm) and raised (4/5). Histologically, the tumors were paucicellular, comprised of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53. This article is protected by copyright. All rights reserved.
    Keywords:  Li-Fraumeni syndrome; Rb; p53; pleomorphic fibroma
  5. J Urol. 2020 Mar 19. 101097JU0000000000001027
    Halstuch D, Ber Y, Kedar D, Golan S, Baniel J, Margel D.
      PURPOSE: Men with germline mutations in DNA-repair genes have a higher risk of developing prostate cancer. Active surveillance (AS) is the preferred treatment modality for low-risk prostate cancer. However, many fear to offer this alternative to men with germline mutations. We now describe the short-term oncologic outcomes of active surveillance in a population of men with a high genetic predisposition for developing prostate cancer.MATERIALS AND METHODS: A prospective cohort of men with germline DNA-repair genes mutations that were diagnosed with grade group 1 prostate cancer. All men were offered AS. Follow-up consisted of PSA every three months, MP-MRI, and an MRI-US fusion confirmatory biopsy within one year of diagnosis. The primary endpoints included treatment- and progression-free survival.
    RESULTS: Eighteen carriers of DNA repair genes were diagnosed with low-risk prostate cancer (BRCA1-8, BRCA2-6, CHEK2-2, Lynch syndrome-2). Of these, 15 patients (83%) initiated AS, and 3 (17%) declined. All but one, were fully compliant with AS protocol (93%). Twenty percent (n=3) upgraded at confirmatory biopsy and were treated. At a median follow up of 28 months (IQR 8.5-42), 80% of patients (n=12) on AS are free from upgrading or radical treatment.
    CONCLUSIONS: Active surveillance may be feasible among carriers diagnosed with low-risk prostate cancer. If embarking on active surveillance, carriers should be very carefully monitored at a specialized clinic, optimizing patient compliance, and minimizing risk. Until larger-scale studies with long term follow-up become available, this option should be cautiously discussed with the patient.
    Keywords:  DNA Repair; Prostatic Neoplasms; Watchful Waiting
  6. Oncologist. 2020 Mar 19.
    Wei Y, Wu J, Gu W, Wang J, Lin G, Qin X, Dai B, Gan H, Ye D, Zhu Y.
      BACKGROUND: Germline DNA damage repair gene mutations (gDDRm) have been found in approximately 12% of patients with metastatic prostate cancer (mPCa). Previous studies of the clinical impact of gDDRm have mainly been in the setting of metastatic castration-resistant prostate cancer (mCRPC). This study aimed to determine the prognostic value of gDDRm in de novo metastatic and castration-sensitive prostate cancer (mCSPC).MATERIALS AND METHODS: We retrospectively collected the records of 139 consecutive men with de novo mCSPC who initially received systemic therapies following guidelines. This included 128 patients who underwent genetic testing at our center and 11 patients referred to our center after being identified as gDDRm carriers. Time to mCRPC was collected. Kaplan-Meier and log-rank analysis were used to analyze the association between gDDRm and clinical outcomes. Survival outcomes were adjusted using multivariable Cox regression models.
    RESULTS: Of the 139 patients with de novo mCSPC, 28 gDDRm carriers were identified. Median time progressing to mCRPC was significantly shorter in patients carrying gDDRm than in those without mutations (8.3 vs 13.2 months; hazard ratio [HR], 2.37; p < .001). Moreover, median progression time was almost halved in BRCA2 carriers (6.3 vs. 13.2 months; HR, 3.73; p < .001). Subgroup analysis revealed that the presence of gDDRm indicated poor therapy response regardless of disease volume and prostate-specific antigen nadir within the first 7 months. Presence of gDDRm remained independently associated with increased risk of progression to mCRPC in multivariate analysis (adjusted HR, 1.98; p = .006).
    CONCLUSION: Our study suggested that positive gDDRm status predicted rapid progression to castration resistance in patients with de novo mCSPC. We propose identifying gDDRm status at the time of diagnosis for mCSPC patients, considering it is the first step of tailoring individualized treatment. In addition, DNA repair genes were a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and our results call for more frontline targeted therapy trials in gDDRm carriers to prolong the progression time.
    IMPLICATIONS FOR PRACTICE: Results of this study suggested that positive germline DNA damage repair gene mutation (gDDRm) status predicted earlier progression to castration resistance in patients with de novo metastatic and castration-sensitive prostate cancer (mCSPC). These findings indicated the importance of intense therapy for some subgroups of mCSPC, especially for mCSPC harboring gDDRm with low-volume disease. Moreover, gDDRm was a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and these findings call for more molecular marker driven trials moving to the mTNPC setting.
    Keywords:  BRCA2; DNA repair genes; De novo metastatic prostate cancer; Germline mutations; Prognostic value
  7. Fam Cancer. 2020 Mar 14.
    Heald B, Hampel H, Church J, Dudley B, Hall MJ, Mork ME, Singh A, Stoffel E, Stoll J, You YN, Yurgelun MB, Kupfer SS, .
      Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.
    Keywords:  Inherited colorectal cancer; Lynch syndrome; Multigene panel testing; Next-generation sequencing; Polyposis; Position statement
  8. Ann Oncol. 2018 Oct;pii: S0923-7534(19)32897-2. [Epub ahead of print]29 Suppl 7 vii12
    Akagi K.
  9. Clin Endocrinol (Oxf). 2020 Mar 17.
    Martins RG, Cunha N, Simões H, Matos MJ, Silva J, Torres I, Rodrigues F, Leite V, Teixeira MR, Bugalho MJ.
      OBJECTIVE: Mutations in the genes coding for succinate dehydrogenase (SDHx) are the most frequent germline alterations in pheochromocytomas and paragangliomas. Evidence for the advantages associated with pre-symptomatic screening for SDHx mutation carriers is scarce. This study describes a nationwide cohort of these mutation carriers and aims to compare patients with clinical manifestations of the disease and those diagnosed through genetic screening.DESIGN: Cross-sectional study.
    PATIENTS: SDHx mutation carriers (n = 118) followed through the Portuguese Oncology referral centers: 41 probands and 77 non-probands.
    MEASUREMENTS: All participants were subjected to biochemical and body imaging examinations for a complete assessment of the extent and spread of disease. Clinical data obtained this way were further analyzed.
    RESULTS: The mean age of this cohort was 44.5 ± 17.4 years, and more than half carried the same founder SDHB mutation. About 50.8% of the mutation carriers developed pheochromocytomas or paragangliomas. Compared to patients diagnosed through genetic screening, those diagnosed clinically were characterized by larger tumors (p < 0.001), more frequent metastases (p = 0.024), were more frequently subjected to surgery (p = 0.011) and radiotherapy (p = 0.013), and had worse outcomes, such as macroscopic positive margins (p = 0.034). Persistent and/or unresectable disease and disease-related mortality were also more frequent in symptomatic patients compared to those diagnosed through genetic screening (p = 0.014).
    CONCLUSIONS: In this nationwide cohort study, a large proportion of mutation carriers were found to develop SDHx-related neoplasia. Genetic testing and subsequent follow-up resulted in the diagnosis of smaller and non-metastatic tumors, fewer treatment procedures, fewer complications, and greater number of disease-free patients.
    Keywords:  SDHx mutations; cross-sectional cohort study; paraganglioma; pheochromocytoma; pre-symptomatic screening
  10. Genes (Basel). 2020 Mar 18. pii: E325. [Epub ahead of print]11(3):
    Klančar G, Blatnik A, Šetrajčič Dragoš V, Vogrič V, Stegel V, Blatnik O, Drev P, Gazič B, Krajc M, Novaković S.
      The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel MLH1 in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in MLH1. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel MLH1 variant as likely pathogenic, we confirmed the LS in this family.
    Keywords:  Lynch syndrome; MMR; isolated PMS2 loss; novel MLH1 variant; segregation analysis
  11. Am J Transl Res. 2020 ;12(2): 612-617
    Tao H, Liu S, Huang D, Han X, Wu X, Shao YW, Hu Y.
      PARP inhibitor (PARPi) therapies have been approved for treating multiple germline BRCA mutated (gBRCAm) advanced cancers including metastatic pancreatic cancer. Although significantly prolonged progression-free survival was observed in gBRCAm pancreatic cancer patients, there was no improved overall survival. The underlined resistant mechanism to PARPi therapy is worth pursuing. Here, we reported a patient with advanced pancreatic cancer harboring a germline deleterious BRCA2 V1804Kfs mutation as well as somatic mutations in KRAS, TP53 and PTEN. Stable disease was achieved with the combination therapy of cisplatin and PARPi olaparib, but the disease quickly progressed after 18 weeks of treatment. Next-generation sequencing (NGS)-based genomic profiling of the liver metastasis and liquid biopsy revealed four newly acquired BRCA2 indel mutations, including two reversion mutations that could potentially restore BRCA2 function in the PARPi-resistant tumor. Our case showed that although initial response to PARPi therapy can be achieved in advanced gBRCAm pancreatic cancer patient, the tumor rapidly evolved to acquire multiple secondary BRCA2 mutations to restore the integrity of DNA repair and confer drug resistance, which may contribute to the unimproved overall survival in pancreatic cancer patients.
    Keywords:  PARP inhibitor; Pancreatic cancer; germline BRCA2 mutation; reversion mutation
  12. Ann Oncol. 2018 Oct;pii: S0923-7534(19)33107-2. [Epub ahead of print]29 Suppl 7 vii40
    Sugano K.
  13. Mol Oncol. 2020 Mar 16.
    Adamson AW, Ding YC, Mendez-Dorantes C, Bailis AM, Stark JM, Neuhausen SL.
      Women who carry pathogenic mutations in BRCA1 and BRCA2 have a lifetime risk of developing breast cancer of up to 80%. However, risk estimates vary in part due to genetic modifiers. We investigated the association of the RAD52 S346X variant as a modifier of the risk of developing breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. The RAD52 S346X allele was associated with a reduced risk of developing breast cancer in BRCA2 carriers [per allele hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.56-0.86; P = 0.0008) and to a lesser extent in BRCA1 carriers (per allele HR = 0.78, 95% CI 0.64-0.97, P = 0.02). We examined how this variant affected DNA repair. Using a reporter system that measures repair of DNA double strand breaks (DSBs) by single-strand annealing (SSA), expression of hRAD52 suppressed the loss of this repair in Rad52-/- mouse embryonic stem cells. When hRAD52 S346X was expressed in these cells, there was a significantly reduced frequency of SSA. Interestingly, expression of hRAD52-S346X also reduced the stimulation of SSA observed upon depletion of BRCA2, demonstrating the reciprocal roles for RAD52 and BRCA2 in the control of DSB repair by SSA. From an immunofluorescence analysis, we observed little nuclear localization of the mutant protein as compared to the wildtype; it is likely that the reduced nuclear levels of RAD52 S346X explain the diminished DSB repair by SSA. Altogether, we identified a genetic modifier that protects against breast cancer in women who carry pathogenic mutations in BRCA2 (P = 0.0008), and to a lesser extent BRCA1 (P = 0.02). This RAD52 mutation causes a reduction in DSB repair by SSA, suggesting that defects in RAD52-dependent DSB repair are linked to reduced tumor risk in BRCA2-mutation carriers.
    Keywords:  BRCA2; RAD52; breast cancer; double-strand break repair; germline mutation; nuclear localization; single-strand annealing