bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–01–30
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing.
  2. Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort.
  3. New Perspectives on the Recurrent Monoallelic Germline Mutations of DNA Repair and Checkpoint Genes and Clinical Variability.
  4. ATM Germline Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics and Potential Therapeutic Implications.
  5. Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants.
  6. De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia.
  7. Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant.
  8. A Case of Triple-Negative Breast Cancer with Germline Pathogenic Variants in Both BRCA1 and BRCA2.
  9. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes.
  1. Ann Oncol. 2022 Jan 21. pii: S0923-7534(22)00015-1. [Epub ahead of print]
    Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing.
    P Terraf, F Pareja, D N Brown, O Ceyhan-Birsoy, M Misyura, S Rana, E O'Reilly, M I Carlo, C Aghajanian, Y Liu, F Derakhshan, G Jayakumaran, B Weigelt, M Walsh, Z Stadler, K Offit, M Ladanyi, M Robson, A Zehir, J S Reis-Filho, D Mandelker.
       BACKGROUND: Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.
    PATIENTS AND METHODS: The detection of germline variants affecting moderate and high penetrance cancer susceptibility genes by tumor-only sequencing was compared to clinical germline testing in 21,333 cancer patients who underwent tumor and germline testing using the FDA-authorized MSK-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.
    RESULTS: In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in cancer susceptibility genes, including 18.8%,12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants, and repetitive element insertions were not detected.
    CONCLUSIONS: Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.
    Keywords:  germline testing; precision medicine; tumor-only sequencing
    DOI:  https://doi.org/10.1016/j.annonc.2022.01.006
  2. Front Oncol. 2021 ;11 789659
    Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort.
    Van Thuan Tran, Sao Trung Nguyen, Xuan Dung Pham, Thanh Hai Phan, Van Chu Nguyen, Huu Thinh Nguyen, Huu Phuc Nguyen, Phuong Thao Thi Doan, Tuan Anh Le, Bao Toan Nguyen, Thanh Xuan Jasmine, Duy Sinh Nguyen, Hong-Dang Luu Nguyen, Ngoc Mai Nguyen, Duy Xuan Do, Vu Uyen Tran, Hue Hanh Thi Nguyen, Minh Phong Le, Yen Nhi Nguyen, Thanh Thuy Thi Do, Dinh Kiet Truong, Hung Sang Tang, Minh-Duy Phan, Hoai-Nghia Nguyen, Hoa Giang, Lan N Tu.
       Background: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.
    Methods: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.
    Results: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.
    Conclusion: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.
    Keywords:  BRCA1 ; carrier frequency; genetic carrier screening; hereditary cancer syndrome; pathogenic variant
    DOI:  https://doi.org/10.3389/fonc.2021.789659
  3. Genet Test Mol Biomarkers. 2022 Jan;26(1): 17-25
    New Perspectives on the Recurrent Monoallelic Germline Mutations of DNA Repair and Checkpoint Genes and Clinical Variability.
    Ibrahim Sahin, Hanife Saat.
      Background: Inherited cancers account for ∼10% of cancer cases. Many hereditary cancers are associated with mutations in DNA repair and checkpoint genes making their clinical surveillance important. Methods: We screened 900 patients using a comprehensive cancer gene panel with the following diagnoses: familial (n = 537, 59.6%), colorectal (n = 117, 13%), breast-ovarian (n = 215, 23.8%), endometrium (n = 12, 1.3%), gastric (n = 11, 1.2%), and thyroid (n = 8, 0.8%). Results: The most commonly mutated genes identified were ATM, MSH6, MUTYH, CHEK2, APC, MLH1, RAD50, PALB2, MSH2, CDH1, and PMS2. The most prevalent heterozygous was MUTYH: c.884C>T(P295L), which was predominant in the breast-ovarian group. Notably, the MUTYH, MSH6, and MSH2 variants showed a higher incidence of extracolonic malignancy. Among the DNA mismatch repair (MMR) genes, MSH6 mutations were the most common, followed by mutations in MLH1, MSH2, PMS2, and EPCAM. Conclusion: These findings offer a new perspective and suggest that, beyond ATM, CHEK2, and PALB2, patients with germline monoallelic mutations in MUTYH, MSH6, APC, CDH1, MHS2, and PMS2 may present with a hereditary breast-ovarian cancer phenotype. Continued developments in assessing and researching new variants of known cancer candidate genes will play an important role in improving individual risk prediction, therapy, and prognosis for familial cancers.
    Keywords:  MUTYH; checkpoint; familial cancer; mismatch repair
    DOI:  https://doi.org/10.1089/gtmb.2021.0108
  4. J Natl Cancer Inst. 2022 Jan 25. pii: djac024. [Epub ahead of print]
    ATM Germline Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics and Potential Therapeutic Implications.
    Tony El Jabbour, Maksym Misyura, Darren Cowzer, Michal Zimmermann, Victoria Rimkunas, Antonio Marra, Fatemeh Derakhshan, Pier Selenica, Megan Parilla, Jeremy S Setton, Ozge Ceyhan-Birsoy, Yelena Kemel, Amanda Catchings, Megha Ranganathan, Geoffrey Y Ku, Yelena Y Janjigian, Michael Zinda, Maria Koehler, Zsofia Stadler, Jinru Shia, Jorge S Reis-Filho, Diana Mandelker.
       BACKGROUND: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified.
    METHODS: We analyzed germline testing results from 23,381 cancer patients undergoing tumor-normal sequencing of which 312 individuals had GEJ adenocarcinoma. Genomic profiles, and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA (siRNA) species in GEJ, esophageal and gastric adenocarcinoma cell lines. All statistical tests were 2-sided.
    RESULTS: Pathogenic/likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity (LOH) of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P<.001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 (100%) vs. 92 (86.8%), P=.04, Fisher's exact test.), A synthetic lethal interaction between siRNA silencing of ATM and ATR was observed in the models analyzed.
    CONCLUSIONS: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk.
    DOI:  https://doi.org/10.1093/jnci/djac024
  5. J Med Genet. 2022 Jan 25. pii: jmedgenet-2021-108169. [Epub ahead of print]
    Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants.
    Benjamin A Lerner, Rosa M Xicola, Nicolette J Rodriguez, Rachid Karam, Xavier Llor.
       BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC's 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.
    METHODS: Medical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria.
    RESULTS: When making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria.
    CONCLUSION: In consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.
    Keywords:  gastrointestinal diseases; genetic carrier screening; genetic predisposition to disease; genetics; medical
    DOI:  https://doi.org/10.1136/jmedgenet-2021-108169
  6. Pediatr Blood Cancer. 2022 Jan 27. e29558
    De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond-Blackfan anemia.
    Daria Fedorova, Galina Ovsyannikova, Maria Kurnikova, Anna Pavlova, Tatiana Konyukhova, Alexey Pshonkin, Nataliya Smetanina.
      Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, associated with mutations in ribosomal protein (RP) genes. Growing data on mutations in non-RP genes in patients with DBA-like phenotype became available over recent years. We describe two patients with the phenotype of DBA (onset of macrocytic anemia within the first year of life, paucity of erythroid precursors in bone marrow) and germline de novo variants in the TP53 gene. Both patients became transfusion independent, probably due to L-leucine therapy. The possible role of TP53 variants should be considered in patients with DBA-like phenotype and no mutations in RP genes.
    Keywords:  Diamond-Blackfan anemia; L-leucine; inherited bone marrow failure; p53
    DOI:  https://doi.org/10.1002/pbc.29558
  7. Front Oncol. 2021 ;11 812656
    Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant.
    Jun Li, Ping Wang, Cuiyun Zhang, Sile Han, Han Xiao, Zhiyuan Liu, Xiaoyan Wang, Weiling Liu, Bing Wei, Jie Ma, Hongle Li, Yongjun Guo.
      Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with "conflicting interpretations of its pathogenicity". Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients' family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.
    Keywords:  BRCA1/2; HBOC; splicing variants; synonymous variants; variants classification
    DOI:  https://doi.org/10.3389/fonc.2021.812656
  8. Case Rep Oncol. 2021 Sep-Dec;14(3):14(3): 1645-1651
    A Case of Triple-Negative Breast Cancer with Germline Pathogenic Variants in Both BRCA1 and BRCA2.
    Miyuki Kitahara, Yasuo Hozumi, Mitsuki Machinaga, Yuka Hayashi.
      We report a rare case of hereditary breast and ovarian cancer syndrome (HBOC) with pathogenic variants in both BRCA1 and BRCA2. The patient was a 78-year-old woman who visited the hospital after noticing a lump in her left breast 6 months before, which gradually increased in size. According to her family history, her maternal aunt developed breast cancer in her 40s. On palpation, a 4-cm large mass was palpated in the upper outer part of the left breast. A needle biopsy revealed invasive ductal carcinoma of the breast, which was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The patient was diagnosed with cT2N0M0 stage IIA, and primary systemic treatment was planned. The patient developed drug-induced interstitial pneumonia after receiving paclitaxel. Although she recovered spontaneously, she did not wish to receive further chemotherapy, and thus surgery was performed. Four months after the surgery, the patient became aware of dyspnea. After a thorough examination, she was diagnosed with postoperative cancer recurrence of the left breast with multiple liver metastases, cancerous peritonitis, multiple bone metastases, and multiple lymph node metastases. Genetic testing was performed, and pathogenic variants were found in both BRAC1 and BRCA2. However, her condition worsened, and she died 8 months after the surgery. BRCA pathogenic variants had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. It is desirable to consider the optimal approach to the treatment of breast cancer in pathogenic variants. In elderly patients with triple-negative breast cancer, HBOC may be suspected, based on biomarkers and family history. It is important to provide information on genetic counseling, genetic testing, and effective treatment plans proactively.
    Keywords:  BRCA1; BRCA2; Recurrence; Triple-negative breast cancer
    DOI:  https://doi.org/10.1159/000520148
  9. JAMA Oncol. 2022 Jan 27.
    Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes.
    Breast Cancer Association Consortium
       Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.
    Objective: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.
    Design, Setting, and Participants: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.
    Exposures: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.
    Main Outcomes and Measures: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.
    Results: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.
    Conclusions and Relevance: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.
    DOI:  https://doi.org/10.1001/jamaoncol.2021.6744
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:18.