Advertisement

Familial Cancer

, Volume 10, Issue 3, pp 545–548 | Cite as

Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer

  • Xiaohong R. Yang
  • Lea Jessop
  • Timothy Myers
  • Laufey Amundadottir
  • Ruth M. Pfeiffer
  • William Wheeler
  • Kristen M. Pike
  • Jeff Yuenger
  • Laurie Burdett
  • Meredith Yeager
  • Stephen J. Chanock
  • Margaret A. Tucker
  • Alisa M. GoldsteinEmail author
Article

Abstract

The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families.

Keywords

CDKN2A PALB2 Familial melanoma Pancreatic cancer Germline mutation 

Notes

Acknowledgments

We are indebted to the participating families, whose generosity and cooperation have made this study possible. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, and Mary Fraser. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Hayward NK (2003) Genetics of melanoma predisposition. Oncogene 22(20):3053–3062 May 19PubMedCrossRefGoogle Scholar
  2. 2.
    Goldstein AM, Chan M, Harland M et al (2006) High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 66(20):9818–9828 Oct 15PubMedCrossRefGoogle Scholar
  3. 3.
    Goldstein AM, Chan M, Harland M et al (2007) Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 44(2):99–106PubMedCrossRefGoogle Scholar
  4. 4.
    Jones S, Hruban RH, Kamiyama M et al (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324(5924):217 Apr 10PubMedCrossRefGoogle Scholar
  5. 5.
    Xia B, Sheng Q, Nakanishi K et al (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22(6):719–729 Jun 23PubMedCrossRefGoogle Scholar
  6. 6.
    The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91(15):1310–1316Google Scholar
  7. 7.
    Goldstein AM, Landi MT, Tsang S, Fraser MC, Munroe DJ, Tucker MA (2005) Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations. Cancer Epidemiol Biomarkers Prev 14(9):2208–2212PubMedGoogle Scholar
  8. 8.
    Goldstein AM, Struewing JP, Chidambaram A, Fraser MC, Tucker MA (2000) Genotype-phenotype relationships in US melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 92(12):1006–1010 Jun 21PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein AM (2004) Familial, melanoma, pancreatic cancer, and germline CDKN2A mutations. Hum Mutat 23(6):630PubMedCrossRefGoogle Scholar
  10. 10.
    Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74(1):106–120PubMedCrossRefGoogle Scholar
  11. 11.
    Pfeiffer RM, Hildesheim A, Gail MH et al (2003) Robustness of inference on measured covariates to misspecification of genetic random effects in family studies. Genet Epidemiol 24(1):14–23PubMedCrossRefGoogle Scholar
  12. 12.
    Dudbridge F, Koeleman BP (2003) Rank truncated product of P-values, with application to genomewide association scans. Genet Epidemiol 25(4):360–366PubMedCrossRefGoogle Scholar
  13. 13.
    Sabbaghian N, Kyle R, Hao A, Hogg D, Tischkowitz M (2010) Mutation analysis of the PALB2 cancer predisposition gene in familial melanoma. Fam Cancer. doi: 10.1007/s10689-010-9405-y
  14. 14.
    Hofstatter EW, Domchek SM, Miron A, Garber J, Wang M, Componeschi K, Boghossian L, Miron PL, Nathanson KL, Tung N (2011) PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. doi: 10.1007/s10689-011-9426-1
  15. 15.
    Stadler ZK, Salo-Mullen E, Sabbaghian N, Simon JA, Zhang L, Olson SH, Kurtz R, Offit K, Foulkes WD, Robson ME, Tischkowitz M (2011) Germline PALB2 mutation analysis in breast-pancreas cancer families. J Med Genet. doi: 10.1136/jmg.2010.087379

Copyright information

© Springer Science+Business Media B.V.(outside the USA) 2011

Authors and Affiliations

  • Xiaohong R. Yang
    • 1
  • Lea Jessop
    • 1
  • Timothy Myers
    • 1
    • 2
  • Laufey Amundadottir
    • 1
  • Ruth M. Pfeiffer
    • 1
  • William Wheeler
    • 3
  • Kristen M. Pike
    • 4
  • Jeff Yuenger
    • 1
    • 2
  • Laurie Burdett
    • 1
    • 2
  • Meredith Yeager
    • 1
    • 2
  • Stephen J. Chanock
    • 1
  • Margaret A. Tucker
    • 1
  • Alisa M. Goldstein
    • 1
    • 5
    Email author
  1. 1.Division of Cancer Epidemiology and GeneticsNational Cancer Institute (NCI), National Institutes of Health, DHHSBethesdaUSA
  2. 2.Core Genotyping FacilityNCI-Frederick, SAIC-Frederick, IncFrederickUSA
  3. 3.Information Management Services, IncRockvilleUSA
  4. 4.Laboratory of Molecular TechnologyNCI-Frederick, SAIC-Frederick, IncFrederickUSA
  5. 5.RockvilleUSA

Personalised recommendations