Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families.
OBJECTIVE
We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation.


METHODS
We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives.


RESULTS
Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95% CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation carriers of 47.8 (95% CI, 28.4-74.7).


CONCLUSIONS
This study shows clear evidence of increased risk of cancers other than melanoma in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with CDKN2A mutations other than p16-Leiden.
de Snoo
Femke A
FA
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Bishop
D Timothy
DT
Bergman
Wilma
W
van Leeuwen
Inge
I
van der Drift
Clasine
C
van Nieuwpoort
Frans A
FA
Out-Luiting
Coby J
CJ
Vasen
Hans F
HF
ter Huurne
Jeanet A C
JA
Frants
Rune R
RR
Willemze
Rein
R
Breuning
Martijn H
MH
Gruis
Nelleke A
NA
D005260:Female; D018703:Founder Effect; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D009377:Multiple Endocrine Neoplasia / Q000453:epidemiology*; D009154:Mutation; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000235:genetics*