Identifying Sequence Variants Contributing to Hereditary Breast and Ovarian Cancer In BRCA1 and BRCA2 Negative Breast and Ovarian Cancer Patients

Overview

Journal Sci Rep

Specialty Science

Date 2019 Dec 29

PMID 31882575

Citations 8

Authors

Elisabeth Jarhelle

Hilde Monica Frostad Riise Stensland

Geir Asmund Myge Hansen

Siri Skarsfjord

Christoffer Jonsrud

Monica Ingebrigtsen

Nina Stromsvik

Marijke Van Ghelue

Affiliations

Soon will be listed here.

Abstract

Families with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC cohort, 101 breast and/or ovarian cancer patients negative for PVs and variants of unknown clinical significance (VUS) in BRCA1/2 were screened for PVs in 94 genes using next-generation sequencing. Sixteen genes were closely scrutinized. Nine different deleterious germline PVs/likely pathogenic variants (LPVs) were identified in seven genes in 12 patients: three in ATM, and one in CHEK2, ERCC5, FANCM, RAD51C, TP53 and WRN. Additionally, 32 different VUSs were identified and these require further characterization. For carriers of PV/LPV in many of these genes, there are no national clinical management programs in Norway. The diversity of genetic risk factors possibly involved in cancer development show the necessity for more knowledge to improve the clinical follow-up of this genetically diverse patient group.

Citing Articles

A comprehensive analysis of germline predisposition to early-onset ovarian cancer.

Horackova K, Zemankova P, Nehasil P, Vocka M, Hovhannisyan M, Matejkova K Sci Rep. 2024; 14(1):16183.

PMID: 39003285 PMC: 11246516. DOI: 10.1038/s41598-024-66324-2.

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?.

Horackova K, Janatova M, Kleiblova P, Kleibl Z, Soukupova J Int J Mol Sci. 2023; 24(23).

PMID: 38069345 PMC: 10707471. DOI: 10.3390/ijms242317020.

Impact of High-to-Moderate Penetrance Genes on Genetic Testing: Looking over Breast Cancer.

Turchiano A, Piglionica M, Martino S, Bagnulo R, Garganese A, De Luisi A Genes (Basel). 2023; 14(8).

PMID: 37628581 PMC: 10454640. DOI: 10.3390/genes14081530.

Spectrum and Frequency of Germline Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

Figlioli G, Billaud A, Wang Q, Bolla M, Dennis J, Lush M Cancers (Basel). 2023; 15(13).

PMID: 37444426 PMC: 10340689. DOI: 10.3390/cancers15133313.

Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases.

Alenezi W, Fierheller C, Serruya C, Revil T, Oros K, Subramanian D Front Oncol. 2023; 13:1111191.

PMID: 36969007 PMC: 10030840. DOI: 10.3389/fonc.2023.1111191.

References

LaDuca H, Stuenkel A, Dolinsky J, Keiles S, Tandy S, Pesaran T . Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014; 16(11):830-7. PMC: 4225457. DOI: 10.1038/gim.2014.40. View

Nielsen F, Hansen T, Sorensen C . Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer. 2016; 16(9):599-612. DOI: 10.1038/nrc.2016.72. View

Castera L, Harter V, Muller E, Krieger S, Goardon N, Ricou A . Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families. Genet Med. 2018; 20(12):1677-1686. DOI: 10.1038/s41436-018-0005-9. View

Rafnar T, Gudbjartsson D, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A . Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011; 43(11):1104-7. DOI: 10.1038/ng.955. View

BELL D, Varley J, Szydlo T, Kang D, Wahrer D, Shannon K . Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 2000; 286(5449):2528-31. DOI: 10.1126/science.286.5449.2528. View

Golmard L, Caux-Moncoutier V, Davy G, Al Ageeli E, Poirot B, Tirapo C . Germline mutation in the RAD51B gene confers predisposition to breast cancer. BMC Cancer. 2013; 13:484. PMC: 4016303. DOI: 10.1186/1471-2407-13-484. View

Grunert M, Dorn C, Schueler M, Dunkel I, Schlesinger J, Mebus S . Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot. Hum Mol Genet. 2014; 23(12):3115-28. DOI: 10.1093/hmg/ddu021. View

Mu W, Lu H, Chen J, Li S, Elliott A . Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. J Mol Diagn. 2016; 18(6):923-932. DOI: 10.1016/j.jmoldx.2016.07.006. View

Tung N, Domchek S, Stadler Z, Nathanson K, Couch F, Garber J . Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016; 13(9):581-8. PMC: 5513673. DOI: 10.1038/nrclinonc.2016.90. View

10.

Tedaldi G, Tebaldi M, Zampiga V, Danesi R, Arcangeli V, Ravegnani M . Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer. Oncotarget. 2017; 8(29):47064-47075. PMC: 5564544. DOI: 10.18632/oncotarget.16791. View

11.

Swisher E, Harrell M, Norquist B, Walsh T, Brady M, Lee M . Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma. JAMA Oncol. 2016; 2(3):370-2. PMC: 4865293. DOI: 10.1001/jamaoncol.2015.6053. View

12.

Caminsky N, Mucaki E, Perri A, Lu R, Knoll J, Rogan P . Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. Hum Mutat. 2016; 37(7):640-52. DOI: 10.1002/humu.22972. View

13.

Park K, Choi H, Suh S, Ki C, Kim J . Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome. Ann Lab Med. 2016; 36(5):463-8. PMC: 4940490. DOI: 10.3343/alm.2016.36.5.463. View

14.

Pinto P, Paulo P, Santos C, Rocha P, Pinto C, Veiga I . Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity. Breast Cancer Res Treat. 2016; 159(2):245-56. DOI: 10.1007/s10549-016-3948-z. View

15.

Dong X, Wang L, Taniguchi K, Wang X, Cunningham J, McDonnell S . Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003; 72(2):270-80. PMC: 379222. DOI: 10.1086/346094. View

16.

Li J, Yang L, Gaur S, Zhang K, Wu X, Yuan Y . Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. DOI: 10.1002/humu.22528. View

17.

Buys S, Sandbach J, Gammon A, Patel G, Kidd J, Brown K . A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 2017; 123(10):1721-1730. DOI: 10.1002/cncr.30498. View

18.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M . ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006; 38(8):873-5. DOI: 10.1038/ng1837. View

19.

Goldgar D, Healey S, Dowty J, Da Silva L, Chen X, Spurdle A . Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011; 13(4):R73. PMC: 3236337. DOI: 10.1186/bcr2919. View

20.

Birch J, Hartley A, Tricker K, Prosser J, Condie A, Kelsey A . Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994; 54(5):1298-304. View