Double heterozygous mutation in the BRCA1 and ATM genes involved in development of primary metachronous tumours: a case report
- 10 Downloads
Between 5 and 10% of cases of breast cancer (BC) are attributable to a genetic susceptibility. The BRCA1 and BRCA2 genes described in the late 1990s are associated with an increased risk of breast and ovarian cancer, and the clinical management of carriers of pathogenic variants in these genes is defined in several clinical guidelines (Paluch-Shimon et al. in Ann Oncol 27(suppl 5):v103–v110, 2016; Llort et al. in Clin Transl Oncol 17(12):956–961, 2015). However, the pathogenic variants in BRCA1 and BRCA2 represent only a third of the causes of hereditary BC (Easton et al. in N Engl J Med 372:2243–2257, 2015). The incorporation of NGS (Next Generation Sequencing) techniques in the genetic diagnosis of this pathology, in addition to minimising the cost and time of analysis, allows the simultaneous study of other genes of high and moderate penetrance (Easton et al. in N Engl J Med 372:2243–2257, 2015; Op. Cit.; Tung et al. in Cancer 121(1):25–33, 2015). To date, there are not many cases or series of patients that describe the co-occurrence of two pathogenic variants in these genes of BC. Cases of double heterozygosis have been described with the presence of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, BLM or NBN (Nomizu et al. in Breast Cancer 22(5):557–61, 2015; Heidemann et al. in Breast Cancer Res Treat 134(3):1229–1239, 2012; Zuradelli et al. in Breast Cancer Res Treat 124(1):251–258, 2010; Sokolenko et al. in Breast Cancer Res Treat 145(2):553–562, 2014).
We report the case of a patient diagnosed with multiple tumours who presented two pathogenic variants in heterozygosis.
Two pathogenic variants, c.5123C > A (p.Ala1708Glu) in the BRCA1 gene and c.2413C > T (p.Arg805X) in the ATM gene were detected in heterozygosis. Said variants were confirmed by Sanger-type sequencing using specific primers.
The implementation of gene panels using NGS in the study of hereditary cancer involves the detection of heterozygous double mutations in genes of high and moderate penetrance for cancer, although with a low frequency.
KeywordsATM BRCA1 Breast cancer Double heterocygote
Compliance with ethical standards
Conflict of interest
All the authors declare that they have no conflicts of interest.
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 1.Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, Senkus E, ESMO Guidelines Committee (2016) Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol 27(suppl 5):v103–v110CrossRefGoogle Scholar
- 3.Easton DF, Pharoah PD, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, Devilee P, Meindl A, Couch FJ, Southey M, Goldgar DE, Evans DG, Chenevix-Trench G, Rahman N, Robson M, Domchek SM, Foulkes WD (2015) Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243–2257CrossRefGoogle Scholar
- 6.Heidemann S, Fischer C, Engel C, Fischer B, Harder L, Schlegelberger B, Niederacher D, Goecke TO, Doelken SC, Dikow N, Jonat W, Morlot S, Schmutzler RC, Arnold NK (2012) Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. Breast Cancer Res Treat 134(3):1229–1239CrossRefGoogle Scholar
- 7.Zuradelli M, Peissel B, Manoukian S, Zaffaroni D, Barile M, Pensotti V, Cavallari U, Masci G, Mariette F, Benski AC, Santoro A, Radice P (2010) Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat 124(1):251–258CrossRefGoogle Scholar
- 8.Sokolenko AP, Bogdanova N, Kluzniak W, Preobrazhenskaya EV, Kuligina ES, Iyevleva AG, Aleksakhina SN, Mitiushkina NV, Gorodnova TV, Bessonov AA, Togo AV, Lubiński J, Cybulski C, Jakubowska A, Dörk T, Imyanitov EN (2014) Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat 145(2):553–562CrossRefGoogle Scholar
- 10.Phuah SY, Looi LM, Hassan N, Rhodes A, Dean S, Taib NA et al (2012) Triple-negative breast cancer and PTEN (phosphatase and tensin homologue) loss are predictors of BRCA1 germline mutations in women with early-onset and familial breast cancer, but not in women with isolated late-onset breast cancer. Breast Cancer Res 14:R142CrossRefGoogle Scholar
- 11.Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev 21:134–147CrossRefGoogle Scholar