Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia
- 584 Downloads
To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population.
Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site.
We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86% for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also identified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites.
Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.
KeywordsBreast cancer Germline mutation BRCA1/2 PALB2 Malaysia
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (DCEG), and Natural Sciences and Engineering Research Council of Canada-Discovery Grant [371758-2009], Canadian Foundation for Innovation, Canada Research Chairs and Cytognomix Inc.
Compliance with ethical standards
Conflicts of interest
PKR is the inventor of US Patent 5867402 and other patents pending, which underlie the prediction and validation of mutations. He cofounded Cytognomix Inc., which is developing software based on this technology for complete genome or exome mutation analysis.
- 6.Wen W, Shu XO, Guo X, Cai Q, Long J, Bolla MK, Michailidou K, Dennis J, Wang Q, Gao YT, Zheng Y, Dunning AM, Garcia-Closas M, Brennan P, Chen ST, Choi JY, Hartman M, Ito H, Lophatananon A, Matsuo K, Miao H, Muir K, Sangrajrang S, Shen CY, Teo SH, Tseng CC, Wu AH, Yip CH, Simard J, Pharoah PD, Hall P, Kang D, Xiang Y, Easton DF, Zheng W (2016) Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry. Breast Cancer Res 18(1):124. doi: 10.1186/s13058-016-0786-1 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (2008) High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 105(44):17079–17084. doi: 10.1073/pnas.0806092105 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Central Statistical Office of Malaysia (2010) Population Census of Malaysia. https://web.archive.org/web/20150301154300/, http://www.statistics.gov.my/portal/download_Population/files/census2010/
- 14.Huck OC, Wahab M (2009) Epidemiology of cancer in sarawak 2001-2005. Sarawak Health Department, MalaysiaGoogle Scholar
- 17.Dean M, Boland J, Yeager M, Im KM, Garland L, Rodriguez-Herrera M, Perez M, Mitchell J, Roberson D, Jones K, Lee HJ, Eggebeen R, Sawitzke J, Bass S, Zhang X, Robles V, Hollis C, Barajas C, Rath E, Arentz C, Figueroa JA, Nguyen DD, Nahleh Z (2015) Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2. Gigascience 4:50. doi: 10.1186/s13742-015-0088-z CrossRefPubMedPubMedCentralGoogle Scholar
- 18.DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43(5):491–498. doi: 10.1038/ng.806 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Mucaki EJ, Caminsky NG, Perri AM, Lu R, Laederach A, Halvorsen M, Knoll JH, Rogan PK (2016) A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med Genom 9:19. doi: 10.1186/s12920-016-0178-5 CrossRefGoogle Scholar
- 21.Rogan PK, Faux BM, Schneider TD (1998) Information analysis of human splice site mutations. Hum Mutat 12(3):153–171. doi: 10.1002/(SICI)1098-1004(1998)12:3<153:AID-HUMU3>3.0.CO;2-I CrossRefPubMedGoogle Scholar
- 26.Vega A, Campos B, Bressac-De-Paillerets B, Bond PM, Janin N, Douglas FS, Domenech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, Diez O (2001) The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat 17(6):520–521. doi: 10.1002/humu.1136 CrossRefPubMedGoogle Scholar
- 27.Peterlongo P, Catucci I, Colombo M, Caleca L, Mucaki E, Bogliolo M, Marin M, Damiola F, Bernard L, Pensotti V, Volorio S, Dall’Olio V, Meindl A, Bartram C, Sutter C, Surowy H, Sornin V, Dondon MG, Eon-Marchais S, Stoppa-Lyonnet D, Andrieu N, Sinilnikova OM, Genesis Mitchell G, James PA, Thompson E, kConFab, Swe B, Marchetti M, Verzeroli C, Tartari C, Capone GL, Putignano AL, Genuardi M, Medici V, Marchi I, Federico M, Tognazzo S, Matricardi L, Agata S, Dolcetti R, Della Puppa L, Cini G, Gismondi V, Viassolo V, Perfumo C, Mencarelli MA, Baldassarri M, Peissel B, Roversi G, Silvestri V, Rizzolo P, Spina F, Vivanet C, Tibiletti MG, Caligo MA, Gambino G, Tommasi S, Pilato B, Tondini C, Corna C, Bonanni B, Barile M, Osorio A, Benitez J, Balestrino L, Ottini L, Manoukian S, Pierotti MA, Renieri A, Varesco L, Couch FJ, Wang X, Devilee P, Hilbers FS, van Asperen CJ, Viel A, Montagna M, Cortesi L, Diez O, Balmana J, Hauke J, Schmutzler RK, Papi L, Pujana MA, Lazaro C, Falanga A, Offit K, Vijai J, Campbell I, Burwinkel B, Kvist A, Ehrencrona H, Mazoyer S, Pizzamiglio S, Verderio P, Surralles J, Rogan PK, Radice P (2015) FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor. Hum Mol Genet 24(18):5345–5355. doi: 10.1093/hmg/ddv251 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR (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. doi: 10.1002/cncr.29010 CrossRefPubMedGoogle Scholar
- 30.Lang GT, Shi JX, Hu X, Zhang CH, Shan L, Song CG, Zhuang ZG, Cao AY, Ling H, Yu KD, Li S, Sun MH, Zhou XY, Huang W, Shao ZM (2017) The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: screening of 2,991 patients and 1,043 controls by next-generation sequencing. Int J Cancer 141(1):129–142. doi: 10.1002/ijc.30692 CrossRefPubMedGoogle Scholar
- 31.Giordano S, Garrett-Mayer E, Mittal N, Smith K, Shulman L, Passaglia C, Gradishar W, Pavone ME (2016) Association of BRCA1 mutations with impaired ovarian reserve: connection between infertility and breast/ovarian cancer risk. J Adolesc Young Adult Oncol 5(4):337–343. doi: 10.1089/jayao.2016.0009 CrossRefPubMedGoogle Scholar