bims-lifras 2020-02-09 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–02–09
thirteen papers selected by
Joanna Zawacka-Pankau

Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test.
BRCA and Beyond: Comprehensive Image-rich Review of Hereditary Breast and Gynecologic Cancer Syndromes.
Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.
Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.
Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer.
PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session.
Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis.
Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings.
Thyroid carcinomas that occur in familial adenomatous polyposis patients recurrently harbor somatic variants in APC, BRAF, and KTM2D.
Impact of hereditary pancreatitis on patients and their families.
Routine plasma-based genotyping to comprehensively detect germline, somatic, and reversion BRCA mutations among patients with advanced solid tumors.
Germline Mutations in Familial Papillary Thyroid Cancer.
Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

Cancer Res Treat. 2020 Feb 04.

Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test.

Hee-Chul Shin, Han-Byoel Lee, Tae-Kyung Yoo, Eun-Shin Lee, Ryong Nam Kim, Boyoung Park, Kyong-Ah Yoon, Charny Park, Eun Sook Lee, Hyeong-Gon Moon, Dong-Young Noh, Sun-Young Kong, Wonshik Han.

   Purpose: Hereditary cancer syndrome means that inherited genetic mutations can increase a person's risk of developing cancer. We assessed the frequency of germline mutations using an NGS-based multiple-gene panel containing 64-cancer predisposing genes in Korean breast cancer patients with clinical features of hereditary breast and ovarian cancer syndrome (HBOC).
Materials and Methods: A total of 64 genes associated with hereditary cancer syndrome were selected for development of an NGS-based multi-gene panel. Targeted sequencing using the multi-gene panel was performed to identify germline mutations in 496 breast cancer patients with clinical features of HBOC who underwent breast cancer surgery between January 2002 and December 2017.
Results: Of 496 patients, 95 patients (19.2%) were found to have 48 deleterious germline mutations in 16 cancer susceptibility genes. The deleterious mutations were found in 39 of 250 patients (15.6%) who had breast cancer and another primary cancer, 38 of 169 patients (22.5%) who had a family history of breast cancer (≥ 2 relatives), 16 of 57 patients (28.1%) who had bilateral breast cancer, and 29 of 84 patients (34.5%) who were diagnosed with breast cancer at younger than 40 years of age. Of the 95 patients with deleterious mutations, 60 patients (63.2%) had BRCA1/2 mutations and 38 patients (40.0%) had non-BRCA1/2 mutations. We detected 2 novel deleterious mutations in BRCA2 and MLH1.
Conclusion: NGS-based multiple-gene panel testing improved the detection rates of deleterious mutations and provided a cost-effective cancer risk assessment.

Keywords:  Breast cancer; Germline mutation; Hereditary breast and ovarian cancer syndrome; Next-generation sequencing

DOI:  https://doi.org/10.4143/crt.2019.559
Radiographics. 2020 Feb 07. 190084

BRCA and Beyond: Comprehensive Image-rich Review of Hereditary Breast and Gynecologic Cancer Syndromes.

Stephanie Histed Chung, Nina Woldenberg, Antoinette R Roth, Rinat Masamed, Wendy Conlon, Joshua G Cohen, Melissa M Joines, Maitraya K Patel.

In addition to the well-characterized BRCA1 and BRCA2 hereditary breast and ovarian cancer syndromes, many other syndromes that are associated with genetic mutations predispose individuals to an increased risk of breast and gynecologic malignancies. Many mutated genes encode for tumor-suppressor products and are inherited in an autosomal dominant manner. Mutations markedly increase an individual's lifetime risk of cancers in different organ systems, depending on the associated syndrome. These syndromes include Lynch syndrome, the most common hereditary cause of endometrial cancer, and Peutz-Jeghers syndrome, which increases the risks of breast cancer, ovarian cancer, and cervical adenoma malignum. Li-Fraumeni syndrome and Cowden syndrome increase the risk of breast cancer, and Gorlin syndrome increases the risk of ovarian fibromas. With advances in genetic testing, clinicians' knowledge and awareness of the numerous additional genes associated with breast and ovarian cancers, such as ATM, CHEK2, and PALB2, are rapidly expanding. Radiologists have essential roles in patient management, which include developing optimal screening protocols for these patients and closely monitoring them for the development or recurrence of disease-specific malignancies. Radiologists' roles continue to increase and evolve as more mutations are identified and high-risk imaging screening recommendations expand to identify these patients. Understanding the epidemiologic, genetic, and pathophysiologic features and the cancers associated with these syndromes enables radiologists to appropriately contribute to patient management, ensure accurate and timely diagnosis, and make syndrome-specific imaging recommendations. ©RSNA, 2020.

DOI: https://doi.org/10.1148/rg.2020190084
Cancer Res Treat. 2020 Jan 06.

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

Min Chul Choi, Sohyun Hwang, Sewha Kim, Sang Geun Jung, Hyun Park, Won Duk Joo, Seung Hun Song, Chan Lee, Tae-Heon Kim, Haeyoun Kang, Hee Jung An.

   Purpose: In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.
Materials and Methods: Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.
Results: BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53 mutation, exhibited better disease-free survival than those with TP53 mutation alone.
Conclusion: DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Keywords:  Epithelial Ovarian Carcinomas; Homologous Recombination Repair; Massively Parallel Sequencing

DOI:  https://doi.org/10.4143/crt.2019.207
J Hum Genet. 2020 Feb 07.

Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.

Chihiro Hata, Hirofumi Nakaoka, Yu Xiang, Dong Wang, Anping Yang, Dahai Liu, Fang Liu, Qingfeng Zou, Li Wei, Ke Zheng, Ituro Inoue, Hua You.

Genetic testing for BRCA1/2 mutations has become the standard clinical practice. Recent findings suggest the clinical significance of multigene panel testing of BRCA1/2 and other cancer-related genes. However, the clinical features of patients with breast cancer with germline mutations identified using multigene panels remain unclear. In this study, DNA samples from 583 Chinese women with breast cancer were subjected to target sequencing for 54 cancer-related genes using a pre-capture pooling method followed by next-generation sequencing. We identified 79 pathogenic germline mutations in 21 cancer-related genes. Forty-five patients (7.7%) harbored BRCA1/2 mutations, and 38 patients (6.5%) carried pathogenic mutations in the remaining 19 genes. PALB2 was the most commonly (1.2%) mutated gene other than BRCA1/2. Most of the identified pathogenic mutations were novel, suggesting mutation screening by using multigene panel testing is important particularly for non-European populations. Mutations in BRCA1/2 and the other cancer-related genes were differentially associated with clinical features. BRCA1 mutation carriers were strongly associated with triple-negative breast cancer (TNBC), whereas BRCA2 mutation carriers were not. Tumors in BRCA1-mutation carriers had a high histological grade. Patients with BRCA2-mutated breast cancers were likely to develop E-cadherin-negative tumors with bone metastases. Furthermore, mutations in PALB2 were strongly associated with TNBC. We demonstrated the usefulness of multigene panel testing and observed that a substantial proportion of patients with breast cancer had hereditary risk factors. Identifying differential associations between mutation status and clinical features will advance our understanding regarding the pathologies of this heterogeneous disease.

DOI: https://doi.org/10.1038/s10038-020-0729-7
JAMA Oncol. 2020 Feb 06. e196400

Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer.

Allison W Kurian, Kevin C Ward, Paul Abrahamse, Ann S Hamilton, Dennis Deapen, Monica Morrow, Reshma Jagsi, Steven J Katz.

Importance: The increasing use of germline genetic testing may have unintended consequences on treatment. Little is known about how women with pathogenic variants in cancer susceptibility genes are treated for breast cancer.
Objective: To determine the association of germline genetic testing results with locoregional and systemic therapy use in women diagnosed with breast cancer.
Design, Setting, and Participants: For this population-based cohort study, data from women aged 20 years or older who were diagnosed with stages 0 to III breast cancer between 2014 and 2016 were accrued from the Surveillance, Epidemiology and End Results (SEER) registries of Georgia and California. The women underwent genetic testing within 3 months after diagnosis and were reported to the Georgia and California SEER registries by December 1, 2017.
Exposures: Pathogenic variant status based on linked results of clinical germline genetic testing by 4 laboratories that did most such testing in the studied regions.
Main Outcomes and Measures: Potential deviation of treatment from practice guidelines was assessed in the following clinical scenarios: (1) surgery: receipt of bilateral mastectomy by women eligible for less extensive unilateral surgery (unilateral breast tumor); (2) radiotherapy: omission in women indicated for postlumpectomy radiotherapy (all lumpectomy recipients except age ≥70 with stage I, estrogen and/or progesterone receptor [ER/PR] positive, ERBB2 [formerly HER2]-negative disease); and (3) chemotherapy: receipt by women eligible to consider chemotherapy omission (stages I-II, ER/PR-positive, ERBB2-negative, and 21-gene recurrence score of 0-30, which was the upper limit of the intermediate risk range during the study years). The adjusted percentage treated and adjusted odds ratio (OR) are reported based on multivariable modeling for each treatment-eligible group.
Results: A total of 20 568 women (17.3%) of 119 198 were eligible (mean [SD] age, 51.4 [12.2]). Compared with women whose test results were negative, those with BRCA1/2 pathogenic variants were more likely to receive bilateral mastectomy for a unilateral tumor (61.7% vs 24.3%; OR, 5.52, 95% CI, 4.73-6.44), less likely to receive postlumpectomy radiotherapy (50.2% vs 81.5%; OR, 0.22, 95% CI, 0.15-0.32), and more likely to receive chemotherapy for early-stage, ER/PR-positive disease (38.0% vs 30.3%; OR, 1.76 (95% CI, 1.31-2.34). Similar patterns were seen with pathogenic variants in other breast cancer-associated genes (ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53) but not with variants of uncertain significance.
Conclusions and Relevance: Women with pathogenic variants in BRCA1/2 and other breast cancer-associated genes were found to have distinct patterns of breast cancer treatment; these may be less concordant with practice guidelines, particularly for radiotherapy and chemotherapy.

DOI: https://doi.org/10.1001/jamaoncol.2019.6400
Pancreas (Fairfax). 2019 ;3(1): e5-e8

PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session.

Rajvi Patel, Daniel Fein, Carolina B Ramirez, Kevin Do, Muhammad W Saif.

  Survival rates for pancreatic cancer remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops. Tumors deficient in deoxyribonucleic acid (DNA) damage repair mechanisms such as BRCA mutants show better responses to platinum based agents, however, such tumors can utilize the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) pathway as a salvage mechanism. Therefore, inhibition of PARP pathway could lead to tumor destruction and synthetic lethality in presence of BRCA mutation. Various PARP inhibitors have been approved for treatment of patients with germline or somatic BRCA mutant breast and ovarian cancer. This provides basis of using PARP inhibitors in patients with pancreatic cancer that harbor BRCA mutation. A recent phase III Pancreas Cancer Olaparib Ongoing (POLO) study showed impressive results with near doubling of progression free survival compared to placebo (7.4 vs 3.8 months). These results highlight the importance of germline testing for all patients with pancreatic cancer and inclusion of additional deficiencies in homologous recombination repair (ATM and PALB2) including BRCA variants of uncertain significance should be further explored.

Keywords:  BRCA1/2; Chemoresistance; DNA damage repair; Genomics; Germline mutations; Pancreatic cancer; Synthetic lethality

DOI:  https://doi.org/10.17140/POJ-3-e011
Pancreatology. 2020 Jan 20. pii: S1424-3903(20)30029-6. [Epub ahead of print]

Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis.

Karianne Fjeld, Emmanuelle Masson, Jin-Huan Lin, Patrick Michl, Tomasz Stokowy, Anny Gravdal, Khadija El Jellas, Solrun J Steine, Dag Hoem, Bente B Johansson, Monica Dalva, Claudia Ruffert, Wen-Bin Zou, Zhao-Shen Li, Pål R Njølstad, Jian-Min Chen, Zhuan Liao, Stefan Johansson, Jonas Rosendahl, Claude Férec, Anders Molven.

   BACKGROUND/OBJECTIVES: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer.
METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry.
RESULTS: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls.
CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.

Keywords:  Carboxyl ester lipase; Carrier frequency; Chronic pancreatitis; Copy number variation; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.pan.2020.01.011
Cancer. 2020 Feb 03.

Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings.

Hannah Maynard, Zsofia K Stadler, Michael F Berger, David B Solit, Michele Ly, Maeve A Lowery, Diana Mandelker, Liying Zhang, Emmett Jordan, Imane El Dika, Yelena Kemel, Marc Ladanyi, Mark E Robson, Eileen M O'Reilly, Ghassan K Abou-Alfa.

   BACKGROUND: With limited information on germline mutations in biliary tract cancers, this study performed somatic and germline testing for patients at Memorial Sloan Kettering Cancer Center with known biliary tract carcinoma with the aim of determining the frequency and range of pathogenic germline alterations (PGAs).
METHODS: Patients with biliary tract carcinoma were consented for somatic tumor and matched blood testing of up to 468 genes via the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing platform. A germline variant analysis was performed on a panel of up to 88 genes associated with an increased predisposition for cancer. Demographic and diagnostic details were collected.
RESULTS: Germline mutations were tested in 131 patients. Intrahepatic cholangiocarcinoma was the most common cancer (63.4%), and it was followed by gallbladder adenocarcinoma (16.8%), extrahepatic cholangiocarcinoma (16%), and otherwise unspecified biliary tract cancer (3.8%). Known and likely PGAs were present in 21 patients (16.0%), with 9.9% harboring a PGA in a high/moderate-penetrance cancer predisposition gene. Among high-penetrance cancer susceptibility genes, PGAs were most commonly observed in BRCA1 and BRCA2 (33.3%), which made up 5.3% of the entire cohort, and they were followed by PALB2, BAP1, and PMS2. Mutations in ATM, MITF, and NBN, moderate-penetrance cancer susceptibility genes, were identified in 1 patient each. There was no observed difference in the types of mutations among the subtypes of biliary tract cancer.
CONCLUSIONS: The frequency of PGAs found was comparable to existing data on the prevalence of germline mutations in other solid tumor types with matched tumor analysis. This provides support for the role of the BRCA1/2, ATM, and BAP1 genes in biliary tract cancer susceptibility.

Keywords:  ATM; BAP1; BRCA1; BRCA2; biliary tract cancer

DOI:  https://doi.org/10.1002/cncr.32740
Thyroid. 2020 Feb 05.

Thyroid carcinomas that occur in familial adenomatous polyposis patients recurrently harbor somatic variants in APC, BRAF, and KTM2D.

Taina Tuulikki Nieminen, Christopher J Walker, Alisa Olkinuora, Luke K Genutis, Margaret O'Malley, Paul E Wakely, Lisa LaGuardia, Laura Koskenvuo, Johanna Arola, Anna Lepisto, Pamela Brock, Ayse Selen Yilmaz, Ann-Kathrin Eisfeld, James Church, Paivi Peltomaki, Albert de la Chapelle.

BACKGROUND: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid carcinoma (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial.
METHODS: Whole genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition.
RESULTS: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.Val600Glu mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed cribriform-morular variant of PTC (PTC-CMV) histology, and all six of these had somatic mutations in APC. Additionally, 9 FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma.
CONCLUSIONS: Our data indicate that FAP-associated PTCs typically have distinct mutations compared to sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.Val600Glu variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of 12 patients in this series) needs further research.

DOI: https://doi.org/10.1089/thy.2019.0561
J Genet Couns. 2020 Feb 05.

Impact of hereditary pancreatitis on patients and their families.

Celeste A Shelton, Robin E Grubs, Chandraprakash Umapathy, Dhiraj Yadav, David C Whitcomb.

  Hereditary pancreatitis (HP), a highly penetrant (~80%) autosomal dominant disease associated with PRSS1 variants, causes acute pancreatitis in childhood and chronic pancreatitis by early adulthood. Other clinical features include pain, diabetes, and risk of pancreatic cancer. HP kindreds were prospectively recruited from 1995 to 2015. At enrollment, study participants completed medical and family history questionnaires, and provided samples for genotyping. Participants were recontacted between 2015 and 2017 and asked to complete a survey on concerns and experiences related to HP, PRSS1 testing, and genetic counseling. Data were analyzed with descriptive and thematic methods. Thirty-nine affected participants with HP and 21 unaffected family members completed the survey. Among unaffected family members, 'worry' and 'helplessness' were frequently described as the most difficult problem in their family because of HP, particularly with regard to pain. Three participants described the impact of drug addiction on their family. 'School or work limitations' was the leading financial concern, with 65.5% (36/55) rating it as 'moderately' or 'extremely important.' Unexpectedly, only 62% (21/34) of affected PRSS1 carriers believed the chance for a parent to pass HP to his or her children was 50%, whereas 18% (6/34) believed the chance was 100%. The impact of HP on individuals and families varied, which may reflect the highly unpredictable nature of HP severity and outcomes. Based on current and previously reported findings, an overview of important issues for genetic counselors to consider for counseling HP families is included.

Keywords:  PRSS1; family; family perspectives; genetic counseling; hereditary pancreatitis; psychosocial; risk perception; thematic analysis

DOI:  https://doi.org/10.1002/jgc4.1221
Clin Cancer Res. 2020 Feb 07. pii: clincanres.2933.2019. [Epub ahead of print]

Routine plasma-based genotyping to comprehensively detect germline, somatic, and reversion BRCA mutations among patients with advanced solid tumors.

Neelima Vidula, Thereasa A Rich, Oliver Sartor, Jennifer Yen, Aaron Hardin, Tracy Nance, Michael B Lilly, Mohammad Amin Nezami, Sandip P Patel, Benedito A Carneiro, Alice Fan, Adam M Brufksy, Barbara A Parker, Benjamin B Bridges, Neeraj Agarwal, Benjamin L Maughan, Victoria M Raymond, Stephen R Fairclough, Richard B Lanman, Aditya Bardia, Massimo Cristofanilli.

PURPOSE: Poly ADP-ribose inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.
METHODS: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay which evaluates single nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.
RESULTS: Among 828 patients, greater than or equal to 1 deleterious BRCA1/2 mutation was detected in 60 (7.2%) patients, including germline (n=42) and somatic (n=18) mutations. Common co-existing mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%) and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9/42 (21.4%) germline BRCA1/2 mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure which contributed to subsequent resistance to PARPi and platinum therapy.
CONCLUSIONS: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical application of these findings to guide precision medicine approaches for advanced malignancies.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-2933
Endocr Pathol. 2020 Feb 08.

Germline Mutations in Familial Papillary Thyroid Cancer.

Marta Sarquis, Debora C Moraes, Luciana Bastos-Rodrigues, Pedro G Azevedo, Adauto V Ramos, Fabiana Versiani Reis, Paula V Dande, Isabela Paim, Eitan Friedman, Luiz De Marco.

  Thyroid cancer, predominantly of papillary histology (PTC), is a common cancer mostly diagnosed sporadically. Hereditary PTC is encountered in ~ 5% of cases and may present at an earlier age, with greater risks of metastasis and recurrence, compared with sporadic cases. The molecular basis of hereditary PTC is unknown in most cases. In this study, the genetic basis of hereditary PTC in three Brazilian families was investigated. Whole exome sequencing (WES) was carried out for probands in each family, and validated, pathogenic/likely pathogenic sequence variants (P/LPSVs) were genotyped in additional family members to establish their putative pathogenic role. Overall, seven P/LPSVs in seven novel genes were detected: p.D283N*ANXA3, p.Y157S*NTN4, p.G172W*SERPINA1, p.G188S*FKBP10, p.R937C*PLEKHG5, p.L32Q*P2RX5, and p.Q76*SAPCD1. These results indicate that these novel genes are seemingly associated with hereditary PTC, but extension and validation in other PTC families are required.

Keywords:  Candidate genes; Hereditary papillary thyroid carcinoma; Inherited predisposition; Whole exome sequencing

DOI:  https://doi.org/10.1007/s12022-020-09607-4
Ann Oncol. 2014 Apr;pii: S0923-7534(19)36500-7. [Epub ahead of print]25(4): 877-883

Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

M T W Teo, L Dyrskjøt, J Nsengimana, C Buchwald, H Snowden, J Morgan, J B Jensen, M A Knowles, G Taylor, J H Barrett, M Borre, T F Ørntoft, D T Bishop, A E Kiltie.

   BACKGROUND: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS).
PATIENTS AND METHODS: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples.
RESULTS: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele.
CONCLUSIONS: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment.

Keywords:  MRE11A; biomarkers; bladder cancer; cystectomy; next-generation sequencing; radiotherapy

DOI:  https://doi.org/10.1093/annonc/mdu014