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Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 1043–1049 | Cite as

FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer

  • Daniel J. Park
  • Fabrice A. Odefrey
  • Fleur Hammet
  • Graham G. Giles
  • Laura Baglietto
  • ABCFS
  • MCCS
  • John L. Hopper
  • Daniel F. Schmidt
  • Enes Makalic
  • Olga M. Sinilnikova
  • David E. Goldgar
  • Melissa C. SoutheyEmail author
Brief Report

Abstract

We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39–1.61], P = 0.50 and OR = 0.74, 95% CI[0.41–1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.

Keywords

Whole-exome sequencing Massively parallel sequencing Breast cancer FAN1 

Notes

Acknowledgments

The Australian Breast Cancer Family Registry was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators. The University of Melbourne (U01 CA69638) contributed data to this study. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organisations imply endorsement by the US government or the BCFR. We extend our thanks to the many women and their families that generously participated in the ABCFS and consented to us accessing their pathology material. We wish to thank Margaret McCredie for key role in the establishment and leadership of the ABCFS in Sydney, Australia. MCS is a National Health and Medical Research Council Senior Research Fellow and Victorian Breast Cancer Research Consortium (VBCRC) group leader. JLH is an Australia Fellow of the National Health and Medical Research Council and a VBCRC Group Leader. This research was supported by a Victorian Life Sciences Computation Initiative (VLSCI) grant number VR0053 on its peak computing facility at the University of Melbourne, an initiative of the Victorian Government.

References

  1. 1.
    Turnbull C, Hines S, Renwick A, Hughes D, Pernet D, Elliott A, Seal S, Warren-Perry M, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Stratton MR, Rahman N (2010) Mutation and association analysis of GEN1 in breast cancer susceptibility. Breast Cancer Res Treat 124:283–288PubMedCrossRefGoogle Scholar
  2. 2.
    Bonnefond A, Froguel P, Vaxillaire M (2010) The emerging genetics of type 2 diabetes. Trends Mol Med 16:407–416PubMedCrossRefGoogle Scholar
  3. 3.
    Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, Goldgar D, Narod SA, Lynch HT, Lenoir GM (1997) Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet 60:486–495PubMedGoogle Scholar
  4. 4.
    Southey MC, Teo ZL, Dowty JG, Odefrey FA, Park DJ, Tischkowitz M, Sabbaghian N, Apicella C, Byrnes GB, Winship I, Breast Cancer Family Registry, KConFab, Baglietto L, Giles GG, Goldgar D, Foulkes WD, Hopper JL (2010) A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 12:R109Google Scholar
  5. 5.
    Mouchawar J, Korch C, Byers T, Pitts TM et al (2010) Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian breast cancer family study. Cancer Res 70:4795–4800PubMedCrossRefGoogle Scholar
  6. 6.
    Neuhausen SL, Ozcelik H, Southey MC et al (2009) BRCA1 and BRCA2 mutation carriers in the breast cancer family registry: an open resource for collaborative research. Breast Cancer Res Treat 116:379–386PubMedCrossRefGoogle Scholar
  7. 7.
    Apicella C, Dowty JG, Dite GS, Jenkins MA et al (2003) Log odds of carrying an ancestral mutation in BRCA1 or BRCA2 for a defined personal and family history in an ashkenazi jewish woman (LAMBDA). Breast Cancer Res 5:R206–R216PubMedCrossRefGoogle Scholar
  8. 8.
    Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H et al (2002) Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94:205–215PubMedCrossRefGoogle Scholar
  9. 9.
    Bernstein JL, Teraoka S, Southey MC, Jenkins MA, Andrulis IL, Knight JA, John EM, Lapinski R, Wolitzer AL, Whittemore AS, West D, Seminara D, Olson ER, Spurdle AB, Chenevix-Trench G, Giles GG, Hopper JL, Concannon P (2006) Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066–6T>G (IVS10–6T>G) from the breast cancer family registry. Hum Mutat 27:1122–1128PubMedCrossRefGoogle Scholar
  10. 10.
    Andrulis IL, Anton-Culver H, Beck J, Bove B et al (2002) Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations. Hum Mutat 20:65–73PubMedCrossRefGoogle Scholar
  11. 11.
    Dite GS, Jenkins MA, Southey MC et al (2003) Familial risks, early-onset breast cancer, and BRCA1 and BRCA2 germline mutations. J Natl Cancer Inst 95:448–457PubMedCrossRefGoogle Scholar
  12. 12.
    Smith LD, Tesoriero AA, Ramus SJ et al (2007) BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study. Eur J Cancer 43:823–827PubMedCrossRefGoogle Scholar
  13. 13.
    Southey MC, Tesoriero AA, Andersen CR, Jennings KM et al (1999) BRCA1 mutations and other sequence variants in a population based sample of Australian women with breast cancer. Br J Cancer 79:34–39PubMedCrossRefGoogle Scholar
  14. 14.
    Le Calvez-Kelm F, Lesueur F, Damiola F, Vallee M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB, Breast Cancer Family Registry, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV (2011) Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res 13:R6PubMedCrossRefGoogle Scholar
  15. 15.
    McCredie MR, Dite GS, Giles GG, Hopper JL (1998) Breast cancer in Australian women under the age of 40. Cancer Causes Control 9:189–198PubMedCrossRefGoogle Scholar
  16. 16.
    Hopper JL, Giles GG, McCredie MR, Boyle P (1994) Background rational and protocol for a case–control-family study of breast cancer. Breast 3:79–86CrossRefGoogle Scholar
  17. 17.
    Hopper JL, Chenevix-Trench G, Jolley DJ et al (1999) Design and analysis issues in a population-based, case–control-family study of the genetic epidemiology of breast cancer and the cooperative family registry for breast cancer studies (CFRBCS). J Natl Cancer Inst Monogr 26:95–100PubMedGoogle Scholar
  18. 18.
    John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, Ziogas A, Andrulis I, Anton-Culver H, Boyd N, Buys SS, Daly MB, O’Malley FP, Santella RM, Southey MC, Venne VL, Venter DJ, West DW, Whittemore AS, Seminara D, The Breast Cancer Family Registry (2004) The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res 6:R375–R389PubMedCrossRefGoogle Scholar
  19. 19.
    Ahmed S, Thomas G, Ghoussaini M, Healey CS et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nature Genet 41:585–590PubMedCrossRefGoogle Scholar
  20. 20.
    Giles GG, English DR (2002) The Melbourne Collaborative Cohort Study. IARC Sci Publ 156:69–70PubMedGoogle Scholar
  21. 21.
    Easton DF, Pooley KA, Dunning AM, Pharoah PDP et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093PubMedCrossRefGoogle Scholar
  22. 22.
    Moldovan G-L, D’Andrea AD (2009) How the fanconi anemia pathway guards the genome. Annu Rev Genet 43:223–249PubMedCrossRefGoogle Scholar
  23. 23.
    Thompson LH, Hinz JM (2009) Cellular and molecular consequences of defective fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights. Mutat Res 668:54–72PubMedCrossRefGoogle Scholar
  24. 24.
    Fanconi G (1967) Familial constitutional panmyelocytopathy, fanconi’s anemia (F.A.). I. clinical aspects. Semin Hematol 4:233–240PubMedGoogle Scholar
  25. 25.
    Schmid W, Fanconi G (1978) Fragility and spiralization anomalies of the chromosomes in three cases, including fraternal twins, with fanconi’s anemia, type estren-dameshek. Cytogenet Cell Genet 20:141–149PubMedCrossRefGoogle Scholar
  26. 26.
    Alter BP, Greene MH, Velazquez I, Rosenberg PS (2003) Cancer in fanconi anemia. Blood 101:2072PubMedCrossRefGoogle Scholar
  27. 27.
    Auerbach AD, Wolman SR (1976) Susceptibility of fanconi’s anemia fibroblasts to chromosome damage by carcinogens. Nature 261:494–496PubMedCrossRefGoogle Scholar
  28. 28.
    Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD (2002) Biallelic inactivation of BRCA2 in fanconi anemia. Science 297:606–609PubMedCrossRefGoogle Scholar
  29. 29.
    Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39:159–161PubMedCrossRefGoogle Scholar
  30. 30.
    Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, Hiom K, De Winter JP, Joenje H (2005) The DNA helicase BRIP1 is defective in fanconi anemia complementation group J. Nat Genet 37:934–935PubMedCrossRefGoogle Scholar
  31. 31.
    Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W (2003) A multiprotein nuclear complex connects fanconi anemia and bloom syndrome. Mol Cell Biol 23:3417–3426PubMedCrossRefGoogle Scholar
  32. 32.
    Gari K, Decaillet C, Stasiak AZ, Stasiak A, Constantinou A (2008) The fanconi anemia protein FANCM can promote branch migration of holliday junctions and replication forks. Mol Cell 29:141–148PubMedCrossRefGoogle Scholar
  33. 33.
    Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ (2010) A genetic screen identifies FAN1, a fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell 39:36–47PubMedCrossRefGoogle Scholar
  34. 34.
    Kratz K, Schöpf KadenS, Sendoel A, Eberhard R, Lademann C, Cannavó E, Sartori AA, Hengartner MO, Jiricny J (2010) Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 142:77–88PubMedCrossRefGoogle Scholar
  35. 35.
    MacKay C, Déclais A-C, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DMJ, Rouse J (2010) Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinylated FANCD2. Cell 142:65–76PubMedCrossRefGoogle Scholar
  36. 36.
    Liu T, Ghosal G, Yuan J, Chen J, Huang J (2010) FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science 329:693–696PubMedCrossRefGoogle Scholar
  37. 37.
    Byrnes GB, Southey MC, Hopper JL (2008) Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res 10:208–214PubMedCrossRefGoogle Scholar
  38. 38.
    Antoniou AC, Wang X, Fredericksen ZS et al (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42:885–892PubMedCrossRefGoogle Scholar
  39. 39.
    Walker L, Fredericksen ZS, Wang X et al (2010) Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res 12:R102PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Daniel J. Park
    • 1
  • Fabrice A. Odefrey
    • 1
  • Fleur Hammet
    • 1
  • Graham G. Giles
    • 2
    • 5
  • Laura Baglietto
    • 2
    • 5
  • ABCFS
    • 3
  • MCCS
    • 4
  • John L. Hopper
    • 5
  • Daniel F. Schmidt
    • 5
  • Enes Makalic
    • 5
  • Olga M. Sinilnikova
    • 6
  • David E. Goldgar
    • 7
  • Melissa C. Southey
    • 1
    Email author
  1. 1.Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
  2. 2.Cancer Epidemiology Centre, The Cancer Council VictoriaMelbourneAustralia
  3. 3.Australian Breast Cancer Family StudyMelbourneAustralia
  4. 4.Melbourne Collaborative Cohort StudyMelbourneAustralia
  5. 5.Centre for Molecular Environmental Genetic and Analytical Epidemiology, School of Population HealthThe University of MelbourneCarltonAustralia
  6. 6.INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche En Cancérologie de Lyon, and Unité Mixte de Génétique Constitutionelle Des Cancers FréquentsCentre Hospitalier Universitaire de Lyon/Centre Léon BérardLyonFrance
  7. 7.Department of DermatologyUniversity of Utah School of MedicineSalt Lake CityUSA

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