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Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia

  • Epidemiology
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Abstract

Purpose

To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population.

Methods

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.

Results

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.

Conclusion

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.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. doi:10.3322/caac.21262

    Article  PubMed  Google Scholar 

  2. Torre LA, Siegel RL, Ward EM, Jemal A (2016) Global cancer incidence and mortality rates and trends–an update. Cancer Epidemiol Biomark Prev 25(1):16–27. doi:10.1158/1055-9965.EPI-15-0578

    Article  Google Scholar 

  3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917. doi:10.1002/ijc.25516

    Article  CAS  PubMed  Google Scholar 

  4. Sung H, Rosenberg PS, Chen WQ, Hartman M, Lim WY, Chia KS, Wai-Kong Mang O, Chiang CJ, Kang D, Ngan RK, Tse LA, Anderson WF, Yang XR (2015) Female breast cancer incidence among Asian and Western populations: more similar than expected. J Natl Cancer Inst. doi:10.1093/jnci/djv107

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lim SE, Back M, Quek E, Iau P, Putti T, Wong JE (2007) Clinical observations from a breast cancer registry in Asian women. World J Surg 31(7):1387–1392. doi:10.1007/s00268-007-9086-3

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25(11):1329–1333. doi:10.1200/JCO.2006.09.1066

    Article  PubMed  PubMed Central  Google Scholar 

  8. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK (2008) Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26(26):4282–4288. doi:10.1200/JCO.2008.16.6231

    Article  PubMed  Google Scholar 

  9. Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948. doi:10.1056/NEJMra1001389

    Article  CAS  PubMed  Google Scholar 

  10. Ferla R, Calo V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A (2007) Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol 18(Suppl 6):vi93–vi98. doi:10.1093/annonc/mdm234

    Article  PubMed  Google Scholar 

  11. Liede A, Narod SA (2002) Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat 20(6):413–424. doi:10.1002/humu.10154

    Article  CAS  PubMed  Google 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

    Article  PubMed  Google 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, Malaysia

  15. Devi CR, Tang TS, Corbex M (2012) Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese, Malay and natives of Sarawak,Malaysia. Int J Cancer 131(12):2869–2877. doi:10.1002/ijc.27527

    Article  CAS  PubMed  Google Scholar 

  16. Horne HN, Beena Devi CR, Sung H, Tang TS, Rosenberg PS, Hewitt SM, Sherman ME, Anderson WF, Yang XR (2015) Greater absolute risk for all subtypes of breast cancer in the US than Malaysia. Breast Cancer Res Treat 149(1):285–291. doi:10.1007/s10549-014-3243-9

    Article  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  Google Scholar 

  20. Shirley BC, Mucaki EJ, Whitehead T, Costea PI, Akan P, Rogan PK (2013) Interpretation, stratification and evidence for sequence variants affecting mRNA splicing in complete human genome sequences. Genom Proteom Bioinform 11(2):77–85. doi:10.1016/j.gpb.2013.01.008

    Article  CAS  Google 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

    Article  CAS  PubMed  Google Scholar 

  22. Mucaki EJ, Shirley BC, Rogan PK (2013) Prediction of mutant mRNA splice isoforms by information theory-based exon definition. Hum Mutat 34(4):557–565. doi:10.1002/humu.22277

    Article  CAS  PubMed  Google Scholar 

  23. Lu R, Mucaki EJ, Rogan PK (2017) Discovery and validation of information theory-based transcription factor and cofactor binding site motifs. Nucleic Acids Res 45(5):e27. doi:10.1093/nar/gkw1036

    Article  CAS  PubMed  Google Scholar 

  24. Halvorsen M, Martin JS, Broadaway S, Laederach A (2010) Disease-associated mutations that alter the RNA structural ensemble. PLoS Genet 6(8):e1001074. doi:10.1371/journal.pgen.1001074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415

    Article  CAS  Google 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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Consortium EP (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74. doi:10.1038/nature11247

    Article  CAS  Google 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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google 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

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, NCI/NIH, Bethesda, Rockville, MD, USA

    Xiaohong R. Yang, Hyuna Sung, Jennifer Guida, Yanzi Xiao, Ana Best, Yi Xie, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Karobi Moitra & Michael Dean

  2. Department of Radiotherapy, Oncology and Palliative Care, Sarawak General Hospital, Kuching, Sarawak, Malaysia

    Beena C. R. Devi & Tieng Swee Tang

  3. Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

    Eliseos J. Mucaki & Peter K. Rogan

  4. Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Lisa Garland, Kristine Jones, Wen Luo & Belynda Hicks

  5. Department of Biology, Trinity Washington University, Washington, DC, USA

    Karobi Moitra

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  1. Xiaohong R. Yang
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Corresponding author

Correspondence to Xiaohong R. Yang.

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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.

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Yang, X.R., Devi, B.C.R., Sung, H. et al. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. Breast Cancer Res Treat 165, 687–697 (2017). https://doi.org/10.1007/s10549-017-4356-8

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