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J Monzon

Publications and source records attributed to J Monzon.

4 recordsLinked to original sources
PubMed1999

Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma.

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.

5' Untranslated Regions↗
PubMed1998

CDKN2A mutations in multiple primary melanomas.

BACKGROUND: Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations. METHODS: We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants. RESULTS: Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma. CONCLUSIONS: Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.

Adult↗
PubMed1998

Role of the cyclin-dependent kinase inhibitor CDKN2A in familial melanoma.

BACKGROUND: Approximately 8 to 12% of melanoma appears to be inherited in an autosomal dominant form. Although most early stage melanomas can be treated successfully by simple surgical excision, patients with advanced disease are rarely cured even with aggressive chemotherapy and/or immunotherapy. OBJECTIVE: There is now compelling evidence that germline mutations of the CDKN2A gene on chromosome 9p21 predispose to melanoma in a subset of melanoma-prone families. In this article the evidence for the role of CDKN2A in the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed. CONCLUSION: The identification and subsequent surveillance of unaffected individuals who have a genetic predisposition to melanoma may lead to the detection of early (curable) melanomas and to a reduction in mortality.

Cell Cycle↗