Genome instability in blood cells of a BRCA1+ breast cancer family

BMC Cancer

Fengxia Xiao³  Yeong C Kim³  Carrie Snyder¹  Hongxiu Wen³  Pei Xian Chen⁵  Jiangtao Luo⁴  Dina Becirovic¹  Bradley Downs³  Kenneth H Cowan²  Henry Lynch¹  San Ming Wang³ 

[1] Hereditary Cancer Center, Department of Preventive Medicine, Creighton University, Omaha, NE 68198, USA

[2] Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68178, USA

[3] Department of Genetics, Cell Biology and Anatomy, Omaha, NE 68198, USA

[4] Department of Biostatistics, College of Public Health, Omaha, NE 68178, USA

[5] Department of Medicine, College of Medicine, Omaha, NE 68178, USA

关键词: Genome instability;    Germline mutation;    Bioinformatics;    Exome sequencing;    Familial breast cancer;    BRCA1+;   

Others  :  858816
DOI  :  10.1186/1471-2407-14-342

 received in 2014-01-17, accepted in 2014-05-07,  发布年份 2014

【 摘 要 】

Background

BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability.

Methods

Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members.

Results

We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo.

Conclusion

Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells.

【 授权许可】

   
2014 Xiao et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Welcsh PL, King MC: BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet 2001, 10:705-713.
• [2]Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990, 250:1684-1689.
• [3]Narod SA, Feunteun J, Lynch HT, Watson P, Conway T, Lynch J, Lenoir GM: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 1991, 338:82-83.
• [4]Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994, 266:66-71.
• [5]U.S. Preventive Services Task Force: Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005, 143:355-361.
• [6]Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002, 108:171-182.
• [7]Stratton MR, Rahman N: The emerging landscape of breast cancer susceptibility. Nat Genet 2008, 40:17-22.
• [8]Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP: Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 1997, 57:1222-1227.
• [9]Tomlinson GE, Chen TT, Stastny VA, Virmani AK, Spillman MA, Tonk V, Blum JL, Schneider NR, Wistuba II, Shay JW, Minna JD, Gazdar AF: Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. Cancer Res 1998, 58:3237-3242.
• [10]Weigman VJ, Chao HH, Shabalin AA, He X, Parker JS, Nordgard SH, Grushko T, Huo D, Nwachukwu C, Nobel A, Kristensen VN, Børresen-Dale AL, Olopade OI, Perou CM: Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival. Breast Cancer Res Treat 2012, 133:865-880.
• [11]Popova T, Manié E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, Delattre O, Sigal-Zafrani B, Bollet M, Longy M, Houdayer C, Sastre-Garau X, Vincent-Salomon A, Stoppa-Lyonnet D, Stern M: Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 2012, 72:5454-5462.
• [12]Konishi H, Mohseni M, Tamaki A, Garay JP, Croessmann S, Karnan S, Ota A, Wong HY, Konishi Y, Karakas B, Tahir K, Abukhdeir AM, Gustin JP, Cidado J, Wang GM, Cosgrove D, Cochran R, Jelovac D, Higgins MJ, Arena S, Hawkins L, Lauring J, Gross AL, Heaphy CM, Hosokawa Y, Gabrielson E, Meeker AK, Visvanathan K, Argani P, Bachman KE, Park BH: Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci U S A 2011, 108:17773-17778.
• [13]Kwei KA, Kung Y, Salari K, Holcomb IN, Pollack JR: Genomic instability in breast cancer: pathogenesis and clinical implications. Mol Oncol 2010, 4:255-266.
• [14]Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX: Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 1999, 22:37-43.
• [15]Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan XY, Ried T, Deng CX: A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene 1998, 17:3115-3124.
• [16]Brodie SG, Xu X, Qiao W, Li WM, Cao L, Deng CX: Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene 2001, 20:7514-7523.
• [17]Puget N, Sinilnikova OM, Stoppa-Lyonnet D, Audoynaud C, Pagès S, Lynch HT, Goldgar D, Lenoir GM, Mazoyer S: An Alu-mediated 6-kb duplication in the BRCA1 gene: a new founder mutation? Am J Hum Genet 1999, 64:300-302.
• [18]The BRCA1 Exon 13 Duplication Screening Group: The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. Am J Hum Genet 2000, 67:207-212.
• [19]Langmead B, Salzberg SL: Fast gapped-read alignment with Bowtie2. Nat Methods 2012, 9:357-359.
• [20]Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, Miller CA, Mardis ER, Ding L, Wilson RK: VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res 2012, 22:568-576.
• [21]McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA: The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010, 20:1297-1303.
• [22]Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data: The sequence alignment/map (SAM) format and SAMtools. Bioinformatics 2009, 25:2078-2079.
• [23]The 1000 Genomes Project Consortium: An integrated map of genetic variation from 1,092 human genomes. Nature 2012, 491:56-65.
• [24]Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010, 7:248-249.
• [25]Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009, 4:1073-1081.
• [26]Wang K, Li M, Hakonarson H: ANNOVAR: Functional annotation of genetic variants from next-generation sequencing data. Nucleic Acids Res 2010, 38:e164.
• [27]Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD: A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res 2012, 22:993-1005.
• [28]Ruthenburg AJ, Li H, Milne TA, Dewell S, McGinty RK, Yuen M, Ueberheide B, Dou Y, Muir TW, Patel DJ, Allis CD: Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell 2011, 145:692-706.
• [29]Buganim Y, Goldstein I, Lipson D, Milyavsky M, Polak-Charcon S, Mardoukh C, Solomon H, Kalo E, Madar S, Brosh R, Perelman M, Navon R, Goldfinger N, Barshack I, Yakhini Z, Rotter V: A novel translocation breakpoint within the BPTF gene is associated with a pre-malignant phenotype. PLoS One 2010, 5:e9657.
• [30]Nakagawa T, Xiong Y: X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression. Mol Cell 2011, 43:381-391.
• [31]Shigekawa T, Ijichi N, Ikeda K, Horie-Inoue K, Shimizu C, Saji S, Aogi K, Tsuda H, Osaki A, Saeki T, Inoue S: FOXP1, an estrogen-inducible transcription factor, modulates cell proliferation in breast cancer cells and 5-year recurrence-free survival of patients with tamoxifen-treated breast cancer. Horm Cancer 2011, 2:286-297.
• [32]Robinson A, Huttley GA, Booth HS, Board PG: Modelling and bioinformatics studies of the human Kappa-class glutathione transferase predict a novel third glutathione transferase family with similarity to prokaryotic 2-hydroxychromene-2-carboxylate isomerases. Biochem J 2004, 379(Pt3):541-552.
• [33]Porter D, Weremowicz S, Chin K, Seth P, Keshaviah A, Lahti-Domenici J, Bae YK, Monitto CL, Merlos-Suarez A, Chan J, Hulette CM, Richardson A, Morton CC, Marks J, Duyao M, Hruban R, Gabrielson E, Gelman R, Polyak K: A neural survival factor is a candidate oncogene in breast cancer. Proc Natl Acad Sci U S A 2003, 100:10931-10936.
• [34]Burwinkel B, Rootwelt T, Kvittingen EA, Chakraborty PK, Kilimann MW: Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in PHKG2 gene. Pediatr Res 2003, 54:834-839.
• [35]Chooniedass-Kothari S, Vincett D, Yan Y, Cooper C, Hamedani MK, Myal Y, Leygue E: The protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha transcriptional activity. FEBS Lett 2010, 584:1174-1180.
• [36]Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012, 490:61-70.
• [37]Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K, Shimizu C, Saji S, Aogi K, Tsuda H, Osaki A, Saeki T, Inoue S, Inoue S: Association of double-positive FOXA1 and FOXP1 immunoreactivities with favorable prognosis of tamoxifen-treated breast cancer patients. Horm Cancer 2012, 3:147-159.
• [38]Hahn WC, Weinberg RA: Rules for making human tumor cells. N Engl J Med 2002, 347:1593-1603.
• [39]Rubin AF, Green P: Mutation patterns in cancer genomes. Proc Natl Acad Sci U S A 2009, 106(51):21766-21870.
• [40]Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW: Cancer genome landscapes. Science 2013, 339(6127):1546-1558.
• [41]Garraway LA, Lander ES: Lessons from the cancer genome. Cell 2013, 153(1):17-37.
• [42]Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A, Nanda S, Druker H, Scherer SW, Malkin D: Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci U S A 2008, 105:11264-11269.
• [43]MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, Jostins L, Habegger L, Pickrell JK, Montgomery SB, Albers CA, Zhang ZD, Conrad DF, Lunter G, Zheng H, Ayub Q, DePristo MA, Banks E, Hu M, Handsaker RE, Rosenfeld JA, Fromer M, Jin M, Mu XJ, Khurana E, Ye K, Kay M, Saunders GI, Suner MM, Hunt T: A systematic survey of loss-of-function variants in human protein-coding genes. Science 2012, 335(6070):823-828.