Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic
C Winter, M P Nilsson, E Olsson, A M George, Y Chen, A Kvist, T Törngren, J Vallon-Christersson, C Hegardt, J Häkkinen, G Jönsson, D Grabau, M Malmberg, U Kristoffersson, M Rehn, S K Gruvberger-Saal, C Larsson, Å Borg, N Loman, L H Saal, C Winter, M P Nilsson, E Olsson, A M George, Y Chen, A Kvist, T Törngren, J Vallon-Christersson, C Hegardt, J Häkkinen, G Jönsson, D Grabau, M Malmberg, U Kristoffersson, M Rehn, S K Gruvberger-Saal, C Larsson, Å Borg, N Loman, L H Saal
Abstract
Background: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear.
Patients and methods: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden.
Results: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years).
Conclusions: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.
Keywords: breast cancer; carrier; germline; mutation; prevalence; somatic.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Figures
References
- Antoniou A, Pharoah PD, Narod S et al. . Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72: 1117–1130.
- Miki Y, Swensen J, Shattuck-Eidens D et al. . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.
- Wooster R, Neuhausen SL, Mangion J et al. . Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994; 265: 2088–2090.
- Futreal PA, Liu Q, Shattuck-Eidens D et al. . BRCA1 mutations in primary breast and ovarian carcinomas. Science 1994; 266: 120–122.
- Gonzalez-Angulo AM, Timms KM, Liu S et al. . Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011; 17: 1082–1089.
- Janatova M, Zikan M, Dundr P et al. . Novel somatic mutations in the BRCA1 gene in sporadic breast tumors. Hum Mutat 2005; 25: 319.
- Khoo US, Ozcelik H, Cheung AN et al. . Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer. Oncogene 1999; 18: 4643–4646.
- Lancaster JM, Wooster R, Mangion J et al. . BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 1996; 13: 238–240.
- Miki Y, Katagiri T, Kasumi F et al. . Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 1996; 13: 245–247.
- Sørlie T, Andersen TI, Bukholm I, Børresen-Dale AL. Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases. Breast Cancer Res Treat 1998; 48: 259–264.
- van der Looij M, Cleton-Jansen AM, van Eijk R et al. . A sporadic breast tumor with a somatically acquired complex genomic rearrangement in BRCA1. Genes Chromosomes Cancer 2000; 27: 295–302.
- Zhang M, Xu Y, Ouyang T et al. . Somatic mutations in the BRCA1 gene in Chinese women with sporadic breast cancer. Breast Cancer Res Treat 2012; 132: 335–340.
- Meric-Bernstam F, Brusco L, Daniels M et al. . Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol 2016; 27: 795–800.
- Burgess M, Puhalla S. BRCA 1/2-mutation related and sporadic breast and ovarian cancers: more alike than different. Front Oncol 2014; 4: 19.
- Wiggans AJ, Cass GK, Bryant A et al. . Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev 2015; 5: CD007929.
- Ledermann J, Harter P, Gourley C et al. . Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–861.
- Lord CJ, Tutt AN, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med 2015; 66: 455–470.
- Eccles DM, Mitchell G, Monteiro AN et al. . BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol 2015; 26: 2057–2065.
- Saal LH, Vallon-Christersson J, Hakkinen J et al. . The Sweden Cancerome Analysis Network—Breast (SCAN-B) Initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. Genome Med 2015; 7: 20.
- Olsson E, Winter C, George A et al. . Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 2015; 7: 1034–1047.
- Koboldt DC, Zhang Q, Larson DE et al. . VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 2012; 22: 568–576.
- Szabo C, Masiello A, Ryan JF, Brody LC. The breast cancer information core: database design, structure, and scope. Hum Mutat 2000; 16: 123–131.
- Landrum MJ, Lee JM, Riley GR et al. . ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 2014; 42: D980–D985.
- Forbes SA, Beare D, Gunasekaran P et al. . COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res 2015; 43: D805–D811.
- Knudson AG., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820–823.
- The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.
- Tutt A, Ellis P, Kilburn L et al. . The TNT trial. In 2014 San Antonio Breast Cancer Symposium. Abstract S3-01 Presented 11 December 2014 2014.
- Guidugli L, Pankratz VS, Singh N et al. . A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res 2013; 73: 265–275.
- Bieche I, Lidereau R. Increased level of exon 12 alternatively spliced BRCA2 transcripts in tumor breast tissue compared with normal tissue. Cancer Res 1999; 59: 2546–2550.
- Rauh-Adelmann C, Lau KM, Sabeti N et al. . Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines. Mol Carcinog 2000; 28: 236–246.
Source: PubMed