Abstract
Background
Breast cancer is the most common malignancy in women and thought to be hereditary
in 10% of patients. Recent next-generation sequencing studies have increased the detection
of pathogenic or likely pathogenic (P/LP) variants in genes other than BRCA1/2 in patients with breast cancer. This study evaluated pathogenic variants, likely
pathogenic variants, and variants of unknown significance in 18 hereditary cancer
susceptibility genes in patients with BRCA1/2-negative breast cancer.
Patients and Methods
This retrospective study included 188 high-risk BRCA1/2-negative patients with breast cancer tested with a multigene cancer panel using next-generation
sequencing.
Results
Among 188 proband cases, 18 variants in 21 patients (11.1%) were classified as P/LP
in PALB2 (n = 6), CHEK2 (n = 5), MUTYH (n = 4), ATM (n = 3), TP53 (n = 2), BRIP1 (n = 1), and MSH2 (n = 1). Three novel P/LP variants were identified. An additional 28 variants were classified
as variants of unknown significance and detected in 30 different patients (15.9%).
Conclusion
This is one of the largest study from Turkey to investigate the mutation spectrum
in non-BRCA hereditary breast cancer susceptibility genes. A multigene panel test
increased the likelihood of identifying a molecular diagnosis in patients with BRCA
1/2-negative breast cancer at risk for a hereditary breast cancer syndrome. More studies
are needed to enable the clinical interpretation of these P/LP variants in hereditary
patients with breast cancer.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic and PersonalSubscribe:
Subscribe to Clinical Breast CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 7-30https://doi.org/10.3322/caac.21387
- Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424https://doi.org/10.3322/caac.21492
- Hereditary breast and ovarian cancer: review and future perspectives.J Mol Med. 2006; 84: 16-28https://doi.org/10.1007/s00109-005-0696-7
- Cancer treatment according to BRCA1 and BRCA2 mutations.Nat Rev Clin Oncol. 2012; 9: 520-528https://doi.org/10.1038/nrclinonc.2012.123
Daly MB PR, Berry M et al (2019) NCCN Clinical practice guide- lines in oncology. In: Genetic/familial high-risk assessment: breast and ovarian version 3. Accessed 17 Jan, 2019.
- Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.Genet Med. 2014; 16: 830-837https://doi.org/10.1038/gim.2014.40
- The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: what are the implications for the management of patients and families?.Oncotarget. 2017; 8: 1957-1971https://doi.org/10.18632/oncotarget.12699
- Beyond BRCA: a case series examining the advent of multigene panel testing.Clin Breast Cancer. 2018; 18: e431-e439https://doi.org/10.1016/j.clbc.2018.03.015
- Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.Int J Cancer. 2020;; 148: 285-295https://doi.org/10.1002/ijc.33199
- Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.Int J Cancer. 2017; 140: 95-102https://doi.org/10.1002/ijc.30428
- Outcomes of retesting BRCA negative patients using multigene panels.Fam Cancer. 2017; 16: 319-328https://doi.org/10.1007/s10689-016-9956-7
- Detection of novel germline mutations for breast cancer in non- BRCA1 /2 families.FEBS J. 2015; 282: 3424-3437https://doi.org/10.1111/febs.13352
- Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer.J Clin Oncol. 2016; 34: 1460-1468https://doi.org/10.1200/JCO.2015.65.0747
- HGVS recommendations for the description of sequence variants: 2016 update.Hum Mutat. 2016; 37: 564-569https://doi.org/10.1002/humu.22981
- Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel.Breast Cancer Res Treat. 2017; 161: 135-142https://doi.org/10.1007/s10549-016-4038-y
- Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.Sci Rep. 2019; 9: 19986https://doi.org/10.1038/s41598-019-55515-x
- Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity.Breast Cancer Res Treat. 2016; 159: 245-256https://doi.org/10.1007/s10549-016-3948-z
- The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: high frequency of FANCM pathogenic variants.Int J Cancer. 2019; 144: 2683-2694https://doi.org/10.1002/ijc.31992
- A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.Cancer. 2017; 123: 1721-1730https://doi.org/10.1002/cncr.30498
- Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer.Oncotarget. 2017; 8: 47064-47075https://doi.org/10.18632/oncotarget.16791
- Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.Breast Cancer Res Treat. 2018; 170: 189-196https://doi.org/10.1007/s10549-018-4726-x
- The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk.npj Breast Cancer. 2017; 3: 1-10https://doi.org/10.1038/s41523-017-0024-8
- Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families.Genet Med. 2018; 20: 1677-1686https://doi.org/10.1038/s41436-018-0005-9
- PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.Nat Genet. 2007; 39: 165-167https://doi.org/10.1038/ng1959
- Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer.Cancer. 2014; 120: 963-967https://doi.org/10.1002/cncr.28504
- Spectrum and clinical relevance of PALB2 germline mutations in 7657 Chinese BRCA1/2-negative breast cancer patients.Breast Cancer Res Treat. 2020; 179: 605-614https://doi.org/10.1007/s10549-019-05483-7
- Current perspectives on CHEK2 mutations in breast cancer.Breast Cancer Targets Ther. 2017; 9: 331-335https://doi.org/10.2147/BCTT.S111394
- PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.J Med Genet. 2016; 53: 800-811https://doi.org/10.1136/jmedgenet-2016-103839
- Ataxia–telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review.Curr Oncol. 2018; 25: e176-e180https://doi.org/10.3747/co.25.3707
- Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.Genet Med. 2015; 17: 630-638https://doi.org/10.1038/gim.2014.176
- Clinical Evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.J Clin Oncol. 2014; 32: 2001-2009https://doi.org/10.1200/JCO.2013.53.6607
- Frequency of mutations in individuals with breast cancer referred for BRCA 1 and BRCA 2 testing using next-generation sequencing with a 25-gene panel.Cancer. 2015; 121: 25-33https://doi.org/10.1002/cncr.29010
- Germline mutations of TP53 gene in breast cancer.Tumor Biol. 2014; 35: 9219-9227https://doi.org/10.1007/s13277-014-2176-6
- Associations between cancer predisposition testing panel genes and breast cancer.JAMA Oncol. 2017; 3: 1190https://doi.org/10.1001/jamaoncol.2017.0424
- BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer.Breast Cancer Res. 2018; 20: 7https://doi.org/10.1186/s13058-018-0935-9
- Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families.Fam Cancer. 2012; 11: 483-491https://doi.org/10.1007/s10689-012-9540-8
- Clinical utility of hereditary cancer panel testing: impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D results on patient management and adherence to provider recommendations.Cancer. 126. 2020: 549-558https://doi.org/10.1002/cncr.32572
- A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function.Clin Cancer Res. 2008; 14: 4672-4680https://doi.org/10.1158/1078-0432.CCR-08-0087
- BRIP-1 germline mutation and its role in colon cancer: presentation of two case reports and review of literature.BMC Med Genet. 2019; 20: 75https://doi.org/10.1186/s12881-019-0812-0
- Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.J Clin Oncol. 2012; 30: 958-964https://doi.org/10.1200/JCO.2011.39.5590
- Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study.J Med Genet. 2015; 52: 553-556https://doi.org/10.1136/jmedgenet-2015-103216
- Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry.J Med Genet. 2017; 54: 742-746https://doi.org/10.1136/jmedgenet-2017-104542
- Breast cancer risk genes — association analysis in more than 113,000 women.N Engl J Med. 2021; 384: 428-439https://doi.org/10.1056/NEJMoa1913948
- Detection of novel germline mutations for breast cancer in non-BRCA1/2 families.FEBS J. 2015; 282: 3424-3437https://doi.org/10.1111/febs.13352
- A population-based study of genes previously implicated in breast cancer.N Engl J Med. 2021; 384: 440-451https://doi.org/10.1056/NEJMoa2005936
- An update on genetic risk assessment and prevention: the role of genetic testing panels in breast cancer.Expert Rev Anticancer Ther. 2019; 19: 787-801https://doi.org/10.1080/14737140.2019.1659730
- Multi gene panel testing for hereditary breast cancer - is it ready to be used?.Med Pharm Reports. 2019; 92: 220-225https://doi.org/10.15386/mpr-1083
Article Info
Publication History
Published online: April 12, 2021
Accepted:
April 5,
2021
Received in revised form:
February 19,
2021
Received:
June 24,
2020
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
