Advertisement

Familial Cancer

, Volume 14, Issue 4, pp 621–628 | Cite as

POLE mutations in families predisposed to cutaneous melanoma

  • Lauren G. Aoude
  • Ellen Heitzer
  • Peter Johansson
  • Michael Gartside
  • Karin Wadt
  • Antonia L. Pritchard
  • Jane M. Palmer
  • Judith Symmons
  • Anne-Marie Gerdes
  • Grant W. Montgomery
  • Nicholas G. Martin
  • Ian Tomlinson
  • Stephen Kearsey
  • Nicholas K. Hayward
Original Article

Abstract

Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

Keywords

Cutaneous melanoma POLE Germline mutation 

Notes

Acknowledgments

The authors would like to thank all the participants of this study. This project was funded by the National Health and Medical Research Council of Australia (NHMRC), the Genomic Medicine and Cancer Themes of the Oxford NIHR Comprehensive Biomedical Research Centre, the Oxford Experimental Cancer Medicine Centre, Cancer Research UK Programme Grant (to IT), and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). LGA was supported by an Australia and New Zealand Banking Group Limited Trustees Ph.D. scholarship. NKH and GWM are supported by fellowships from the NHMRC. Work in SEK’s group is supported by a MRC Grant MR/L016591/1. ALP is supported by Cure Cancer Australia and Rio Tinto Ride to Conquer Cancer.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10689_2015_9826_MOESM1_ESM.docx (995 kb)
Supplementary material 1 (DOCX 996 kb)

References

  1. 1.
    Gruis NA, van der Velden PA, Sandkuijl LA et al (1995) Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet 10(3):351–353. doi: 10.1038/ng0795-351 CrossRefPubMedGoogle Scholar
  2. 2.
    Hussussian CJ, Struewing JP, Goldstein AM et al (1994) Germline p16 mutations in familial melanoma. Nat Genet 8(1):15–21. doi: 10.1038/ng0994-15 CrossRefPubMedGoogle Scholar
  3. 3.
    MacGeoch C, Bishop JA, Bataille V et al (1994) Genetic heterogeneity in familial malignant melanoma. Hum Mol Genet 3(12):2195–2200CrossRefPubMedGoogle Scholar
  4. 4.
    Soufir N, Avril MF, Chompret A et al (1998) Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet 7(2):209–216CrossRefPubMedGoogle Scholar
  5. 5.
    Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. http://evs.gs.washington.edu/EVS/. Accessed 27 Feb 2014, Cited 14 June 2013
  6. 6.
    Walker GJ, Hussussian CJ, Flores JF et al (1995) Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet 4(10):1845–1852CrossRefPubMedGoogle Scholar
  7. 7.
    Zuo L, Weger J, Yang Q et al (1996) Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12(1):97–99. doi: 10.1038/ng0196-97 CrossRefPubMedGoogle Scholar
  8. 8.
    Robles-Espinoza CD, Harland M, Ramsay AJ et al (2014) POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. doi: 10.1038/ng.2947 PubMedCentralPubMedGoogle Scholar
  9. 9.
    Aoude LG, Pritchard AL, Robles-Espinoza CD et al (2015) Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. doi: 10.1093/jnci/dju408 PubMedGoogle Scholar
  10. 10.
    Palles C, Cazier JB, Howarth KM et al (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45(2):136–144. doi: 10.1038/ng.2503 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Baxter AJ, Hughes MC, Kvaskoff M et al (2008) The Queensland Study of Melanoma: environmental and genetic associations (Q-MEGA); study design, baseline characteristics, and repeatability of phenotype and sun exposure measures. Twin Res Hum Genet 11(2):183–196. doi: 10.1375/twin.11.2.183 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Aitken JF, Green AC, MacLennan R, Youl P, Martin NG (1996) The Queensland Familial Melanoma Project: study design and characteristics of participants. Melanoma Res 6(2):155–165CrossRefPubMedGoogle Scholar
  13. 13.
    Whiteman DC, Valery P, McWhirter W, Green AC (1997) Risk factors for childhood melanoma in Queensland, Australia. Int J Cancer 70(1):26–31CrossRefPubMedGoogle Scholar
  14. 14.
    Whiteman D, Valery P, McWhirter W, Green A (1995) Incidence of cutaneous childhood melanoma in Queensland, Australia. Int J Cancer 63(6):765–768CrossRefPubMedGoogle Scholar
  15. 15.
    Youl P, Aitken J, Hayward N et al (2002) Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia. Int J Cancer 98(1):92–98CrossRefPubMedGoogle Scholar
  16. 16.
    Whiteman DC, Parsons PG, Green AC (1998) p53 expression and risk factors for cutaneous melanoma: a case-control study. Int J Cancer 77(6):843–848CrossRefPubMedGoogle Scholar
  17. 17.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25(14):1754–1760. doi: 10.1093/bioinformatics/btp324 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Li H, Handsaker B, Wysoker A et al (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079. doi: 10.1093/bioinformatics/btp352 PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Horn S, Figl A, Rachakonda PS et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339(6122):959–961. doi: 10.1126/science.1230062 CrossRefPubMedGoogle Scholar
  21. 21.
    Kamb A, Shattuck-Eidens D, Eeles R et al (1994) Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8(1):23–26. doi: 10.1038/ng0994-22 CrossRefPubMedGoogle Scholar
  22. 22.
    Bahuau M, Vidaud D, Jenkins RB et al (1998) Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res 58(11):2298–2303PubMedGoogle Scholar
  23. 23.
    Moreno S, Klar A, Nurse P (1991) Molecular genetic analysis of the fission yeast Schizosaccharomyces pombe. Methods Enzymol 194:795–823CrossRefPubMedGoogle Scholar
  24. 24.
    Bahler J, Wu JQ, Longtine MS et al (1998) Heterologous modules for efficient and versatile PCR-based gene targeting in Schizosaccharomyces pombe. Yeast 14(10):943–951CrossRefPubMedGoogle Scholar
  25. 25.
    Marti TM, Mansour AA, Lehmann E, Fleck O (2003) Different frameshift mutation spectra in non-repetitive DNA of MutSalpha- and MutLalpha-deficient fission yeast cells. DNA Repair (Amst) 2(5):571–580CrossRefGoogle Scholar
  26. 26.
    Hall BM, Ma CX, Liang P, Singh KK (2009) Fluctuation analysis CalculatOR: a web tool for the determination of mutation rate using Luria–Delbruck fluctuation analysis. Bioinformatics 25(12):1564–1565. doi: 10.1093/bioinformatics/btp253 PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Shevelev IV, Hubscher U (2002) The 3′5′ exonucleases. Nat Rev Mol Cell Biol 3(5):364–376. doi: 10.1038/nrm804 CrossRefPubMedGoogle Scholar
  28. 28.
    Jain R, Rajashankar KR, Buku A et al (2014) Crystal structure of yeast DNA polymerase epsilon catalytic domain. PLoS ONE 9(4):e94835. doi: 10.1371/journal.pone.0094835 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Hogg M, Osterman P, Bylund GO et al (2014) Structural basis for processive DNA synthesis by yeast DNA polymerase varepsilon. Nat Struct Mol Biol 21(1):49–55. doi: 10.1038/nsmb.2712 CrossRefPubMedGoogle Scholar
  30. 30.
    Morrison A, Sugino A (1994) The 3′ → 5′ exonucleases of both DNA polymerases δ and ε participate in correcting errors of DNA replication in Saccharomyces cerevisiae. Mol Gen Genet 242(3):289–296CrossRefPubMedGoogle Scholar
  31. 31.
    Albertson TM, Ogawa M, Bugni JM et al (2009) DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci USA 106(40):17101–17104. doi: 10.1073/pnas.0907147106 PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Rohlin A, Zagoras T, Nilsson S et al (2014) A mutation in POLE predisposing to a multi-tumour phenotype. Int J Oncol 45(1):77–81. doi: 10.3892/ijo.2014.2410 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Lauren G. Aoude
    • 1
  • Ellen Heitzer
    • 2
  • Peter Johansson
    • 1
  • Michael Gartside
    • 1
  • Karin Wadt
    • 4
  • Antonia L. Pritchard
    • 1
  • Jane M. Palmer
    • 1
  • Judith Symmons
    • 1
  • Anne-Marie Gerdes
    • 4
  • Grant W. Montgomery
    • 1
  • Nicholas G. Martin
    • 1
  • Ian Tomlinson
    • 5
  • Stephen Kearsey
    • 3
  • Nicholas K. Hayward
    • 1
  1. 1.QIMR Berghofer Medical Research InstituteBrisbaneAustralia
  2. 2.Institut für HumangenetikMedizinische Universität GrazGrazAustria
  3. 3.Department of ZoologyUniversity of OxfordOxfordUK
  4. 4.Department of Clinical GeneticsRigshospitaletCopenhagenDenmark
  5. 5.Molecular and Population Genetics Laboratory and Genomic Medicine Theme Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK

Personalised recommendations