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Prospective risk of cancer in CDKN2A germline mutation carriers
  1. A M Goldstein1,
  2. J P Struewing2,
  3. M C Fraser1,
  4. M W Smith3,
  5. M A Tucker1
  1. 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA
  2. 2Laboratory of Population Genetics, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA
  3. 3Laboratory of Genomic Diversity, Center for Cancer Research and Basic Research Program, SAIC Frederick, National Cancer Institute at Frederick, NIH, DHHS, Frederick, MD 21702, USA
  1. Correspondence to:
 Dr A M Goldstein
 Genetic Epidemiology Branch/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd., MSC 7236, Bethesda, MD 20892-7236, USA; goldsteaexchange.nih.gov

Abstract

Background: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family’s CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment.

Methods: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained (that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4–26 years starting in the 1970s.

Results: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/Exp = 12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks.

Conclusions: Differences in CDKN2A–non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences.

  • CDKN2A
  • familial melanoma
  • pancreatic cancer
  • prospective risk
  • CI, confidence intervals
  • SIR, standardised incidence ratios

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Footnotes

  • This publication has been funded in part with funds from the National Cancer Institute, NIH, DHHS, Contract No. NO1-CO-12400.

  • Conflict of interest: none declared.