Thus the addition of activating ras mutations to a melanoma cell line already deficient in p16 leads to enhanced proliferation, survival and migration in vitro and to enhanced subcutaneous tumour formation in vivo.
We have also sequenced exon 2 of the recently identified candidate tumour suppressor gene, p16, in six individuals and found no evidence for germline mutations in this region of the p16 gene in our families with inherited malignant melanoma.
Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS).
GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM).
Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation.
Our data suggest that the P48T mutation of p16 is a strong melanoma-predisposing factor, but the fact that the heterozygous mutant parents have not yet exhibited melanoma or atypical moles indicates that the penetrance of this allele might depend on modifying factors.
Participants in all groups continued to rate photoprotection as highly effective in reducing melanoma risk and reported decreased beliefs that carrying the p16 mutation would inevitably lead to the development of melanoma.
The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM.
This partial functional defect may complement the clearly defective p16 del (62-69) mutant and thus contribute to melanoma development in patients carrying the 24bp deletion in CDKN2A.
We conclude that HNSCC in young individuals should prompt clinicians to obtain a family history and consider that the patient may have a germline p16 defect that could predispose them to other cancers, including melanoma and pancreatic cancer.
We compared the gene expression profile of SFs from FM individuals with two distinct CDKN2A/p16 mutations (V126D-p16 and R87P-p16) with the gene expression profile of SFs from age-matched individuals without p16 mutations and with no family history of melanoma.
Taken together with a predominance of UV-induced mutations in the CDKN2/ p16 gene demonstrated in melanoma cell lines, our data support a role of sunlight exposure in the etiology of malignant melanoma.
In an example presented regarding a planned study of the p16 gene and its role in melanoma, a conventional case-control study may require up to 70 times as many subjects to achieve equivalent precision to the study of second primaries.
In summary, our results show frequent involvement of the p16 gene in familial melanoma and confirm the role of the CDK4 gene as a melanoma-predisposing gene.
These studies reveal that LOH and homozygous deletion can affect 9p21 and the p16 locus early in putative precursor lesions of melanoma, even prior to the establishment of cytologically evident aberrant histology.
Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations in both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation.