Advertisement

Breast Cancer Research and Treatment

, Volume 134, Issue 2, pp 543–547 | Cite as

Analysis of KLLN as a high-penetrance breast cancer predisposition gene

  • Ella R. Thompson
  • Kylie L. Gorringe
  • David Y. H. Choong
  • Diana M. Eccles
  • kConFab
  • Gillian Mitchell
  • Ian G. Campbell
Preclinical Study

Abstract

KLLN is a p53 target gene with DNA binding function and represents a highly plausible candidate breast cancer predisposition gene. We screened for predisposing variants in 860 high-risk breast cancer families using high resolution melt analysis. A germline c.339_340delAG variant predicted to cause premature termination of the protein after 57 alternative amino acid residues was identified in 3/860 families who tested negative for BRCA1 and BRCA2 mutations and in 1/84 sporadic breast cancer cases. However, the variant was also detected in 2/182 families with known BRCA1 or BRCA2 mutations and in 2/464 non-cancer controls. Furthermore, loss of the mutant allele was detected in 2/2 breast tumors. Our data suggest that pathogenic mutations in KLLN are rare in breast cancer families and the c.339_340delAG variant does not represent a high-penetrance breast cancer risk allele.

Keywords

Familial breast cancer Germline Mutation BRCAX KILLIN 

Notes

Acknowledgments

This work was supported by the Victorian Breast Cancer Research Consortium.

Conflicts of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Mann GJ, Thorne H, Balleine RL, Butow PN, Clarke CL, Edkins E, Evans GM, Fereday S, Haan E, Gattas M, Giles GG, Goldblatt J, Hopper JL, Kirk J, Leary JA, Lindeman G, Niedermayr E, Phillips KA, Picken S, Pupo GM, Saunders C, Scott CL, Spurdle AB, Suthers G, Tucker K, Chenevix-Trench G (2006) Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res 8(1):R12. doi: 10.1186/bcr1377 PubMedCrossRefGoogle Scholar
  2. 2.
    Cho YJ, Liang P (2008) Killin is a p53-regulated nuclear inhibitor of DNA synthesis. Proc Natl Acad Sci USA 105(14):5396–5401. doi: 10.1073/pnas.0705410105 PubMedCrossRefGoogle Scholar
  3. 3.
    Bennett KL, Mester J, Eng C (2010) Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA 304(24):2724–2731. doi: 10.1001/jama.2010.1877 PubMedCrossRefGoogle Scholar
  4. 4.
    Eccles DM, Englefield P, Soulby MA, Campbell IG (1998) BRCA1 mutations in southern England. Br J Cancer 77:2199–2203PubMedCrossRefGoogle Scholar
  5. 5.
    Bryan EJ, Watson RH, Davis M, Hitchcock A, Foulkes WD, Campbell IG (1996) Localization of an ovarian cancer tumor suppressor gene to a 0.5-cM region between D22S284 and CYP2D, on chromosome 22q. Cancer Res 56(4):719–721PubMedGoogle Scholar
  6. 6.
    Baxter SW, Choong DY, Eccles DM, Campbell IG (2001) Polymorphic variation in CYP19 and the risk of breast cancer. Carcinogenesis 22(2):347–349PubMedCrossRefGoogle Scholar
  7. 7.
    Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386PubMedGoogle Scholar
  8. 8.
    Gorringe KL, Choong DY, Williams LH, Ramakrishna M, Sridhar A, Qiu W, Bearfoot JL, Campbell IG (2008) Mutation and methylation analysis of the chromodomain-helicase-DNA binding 5 gene in ovarian cancer. Neoplasia 10(11):1253–1258PubMedGoogle Scholar
  9. 9.
    Jacobs S, Thompson ER, Nannya Y, Yamamoto G, Pillai R, Ogawa S, Bailey DK, Campbell IG (2007) Genome-wide, high-resolution detection of copy number, loss of heterozygosity, and genotypes from formalin-fixed, paraffin-embedded tumor tissue using microarrays. Cancer Res 67(6):2544–2551. doi: 10.1158/0008-5472.CAN-06-3597 PubMedCrossRefGoogle Scholar
  10. 10.
    Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68(4):820–823PubMedCrossRefGoogle Scholar
  11. 11.
    Cavenee WK, Hansen MF, Nordenskjold M, Kock E, Maumenee I, Squire JA, Phillips RA, Gallie BL (1985) Genetic origin of mutations predisposing to retinoblastoma. Science 228(4698):501–503PubMedCrossRefGoogle Scholar
  12. 12.
    Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11(5):863–874. doi: 10.1101/gr.176601 PubMedCrossRefGoogle Scholar
  13. 13.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. doi: 10.1038/nmeth0410-248 PubMedCrossRefGoogle Scholar
  14. 14.
    Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, Mooney SD, Radivojac P (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25(21):2744–2750. doi: 10.1093/bioinformatics/btp528 PubMedCrossRefGoogle Scholar
  15. 15.
    Ferrer-Costa C, Gelpi JL, Zamakola L, Parraga I, de la Cruz X, Orozco M (2005) PMUT: a web-based tool for the annotation of pathological mutations on proteins. Bioinformatics 21(14):3176–3178PubMedCrossRefGoogle Scholar
  16. 16.
    Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576. doi: 10.1038/nmeth0810-575 PubMedCrossRefGoogle Scholar
  17. 17.
    Bromberg Y, Rost B (2007) SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res 35(11):3823–3835. doi: 10.1093/nar/gkm238 PubMedCrossRefGoogle Scholar
  18. 18.
    The 1000 Genomes Project Consortium (2010) A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073. doi: 10.1038/nature09534 CrossRefGoogle Scholar
  19. 19.
    Haga H, Yamada R, Ohnishi Y, Nakamura Y, Tanaka T (2002) Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome. Single-nucleotide polymorphism. J Hum Genet 47(11):605–610. doi: 10.1007/s100380200092 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Ella R. Thompson
    • 1
  • Kylie L. Gorringe
    • 1
    • 2
  • David Y. H. Choong
    • 1
  • Diana M. Eccles
    • 3
  • kConFab
    • 4
  • Gillian Mitchell
    • 5
  • Ian G. Campbell
    • 1
    • 2
  1. 1.VBCRC Cancer Genetics LaboratoryPeter MacCallum Cancer CentreEast MelbourneAustralia
  2. 2.Department of Pathology and Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia
  3. 3.Cancer Sciences Division, Faculty of MedicineUniversity of Southampton, Princess Anne HospitalSouthamptonUK
  4. 4.Kathleen Cuningham Foundation for Research into Familial Breast Cancer (kConFab)Peter MacCallum Cancer CentreEast MelbourneAustralia
  5. 5.Familial Cancer CentrePeter MacCallum Cancer CentreEast MelbourneAustralia

Personalised recommendations