Abstract
Purpose
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).
Methods
We report the case of a patient diagnosed with multiple tumours who presented two pathogenic variants in heterozygosis.
Results
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.
Conclusions
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.
This is a preview of subscription content, log in via an institution to check access.
References
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–v110
Llort G, Chirivella I, Morales R, Serrano R, Sanchez AB, Teulé A, Lastra E, Brunet J, Balmaña J, Graña B, SEOM Hereditary Cancer Working Group (2015) SEOM clinical guidelines in hereditary breast and ovarian cancer. Clin Transl Oncol 17(12):956–961
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 372:2243–2257
Tung N, Battelli C, Allen B et al (2015) Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 121(1):25–33
Nomizu T, Matsuzaki M, Katagata N, Kobayashi Y, Sakuma T, Monma T, Saito M, Watanabe F, Midorikawa S, Yamaguchi Y (2015) A case of familial breast cancer with double heterozygosity for BRCA1 and BRCA2 genes. Breast Cancer 22(5):557–561
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):1229–1239
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):251–258
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):553–562
Kuchenbaecker KB, Hopper JL, Barnes DR et al (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317(23):2402–2416
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:R142
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 21:134–147
Jacqueline Mersch MS (2015) Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121(2):269–275
Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286:1162–1166
Couch FJ, Shimelis H, Hu Ch et al (2017) Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 3(9):1190–1196
Bowen TJ, Yakushiji H, Montagna C, Jain S, Ried T, Wynshaw-Boris A (2005) Atm heterozygosity cooperates with loss of Brca1 to increase the severity of mammary gland cancer and reduce ductal branching. Cancer Res 65(19):8736–8746
Su F, Smilenov LB, Ludwig T et al (2010) Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis. Radiat Oncol 5:15–23
Wang J, Su F, Smilenov LB, Zhou L, Hu W, Ding N, Zhou G (2011) Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity. Radiat Oncol 6(1):96
Sokolenko AP, Bogdanova N, Kluzniak W et al (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):553–562
Heidemann S, Fischer C, Engel C et al (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 134:1229–1239
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All the authors declare that they have no conflicts of interest.
Ethical approval
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
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Andrés, R., Menao, S., Arruebo, M. et al. Double heterozygous mutation in the BRCA1 and ATM genes involved in development of primary metachronous tumours: a case report. Breast Cancer Res Treat 177, 767–770 (2019). https://doi.org/10.1007/s10549-019-05343-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-019-05343-4