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Erschienen in: Breast Cancer Research and Treatment 3/2017

29.06.2017 | Epidemiology

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

verfasst von: Xiaohong R. Yang, Beena C. R. Devi, Hyuna Sung, Jennifer Guida, Eliseos J. Mucaki, Yanzi Xiao, Ana Best, Lisa Garland, Yi Xie, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Peter K. Rogan, Michael Dean

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2017

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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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Literatur
4.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
10.
12.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
14.
Zurück zum Zitat Huck OC, Wahab M (2009) Epidemiology of cancer in sarawak 2001-2005. Sarawak Health Department, Malaysia Huck OC, Wahab M (2009) Epidemiology of cancer in sarawak 2001-2005. Sarawak Health Department, Malaysia
15.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
16.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
17.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat 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 CrossRef 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 CrossRef
20.
Zurück zum Zitat 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 CrossRef 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 CrossRef
23.
25.
Zurück zum Zitat Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415CrossRef Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31(13):3406–3415CrossRef
26.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
27.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
30.
Zurück zum Zitat 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 CrossRefPubMed 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 CrossRefPubMed
31.
Zurück zum Zitat 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 CrossRefPubMedPubMedCentral 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 CrossRefPubMedPubMedCentral
Metadaten
Titel
Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia
verfasst von
Xiaohong R. Yang
Beena C. R. Devi
Hyuna Sung
Jennifer Guida
Eliseos J. Mucaki
Yanzi Xiao
Ana Best
Lisa Garland
Yi Xie
Nan Hu
Maria Rodriguez-Herrera
Chaoyu Wang
Kristine Jones
Wen Luo
Belynda Hicks
Tieng Swee Tang
Karobi Moitra
Peter K. Rogan
Michael Dean
Publikationsdatum
29.06.2017
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 3/2017
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4356-8

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