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Mutation screening of the CDKN2A promoter in melanoma families
Author(s) -
Harland Mark,
Holland Elizabeth A.,
Ghiorzo Paola,
Mantelli Michela,
BianchiScarrà Giovanna,
Goldstein Alisa M.,
Tucker Margaret A.,
Ponder Bruce A.J.,
Mann Graham J.,
Bishop D. Timothy,
Newton Bishop Julia
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/(sici)1098-2264(200005)28:1<45::aid-gcc6>3.0.co;2-f
Subject(s) - cdkn2a , genetics , germline mutation , biology , melanoma , population , genetic predisposition , germline , linkage disequilibrium , cancer research , mutation , genotype , cancer , gene , medicine , haplotype , environmental health
Germline mutations of CDKN 2 A , at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN 2 A . It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN 2 A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A‐191G and A‐493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A‐493T variant appeared to be in linkage disequilibrium with the previously described CDKN 2 A polymorphism Ala148Thr. The variant G‐735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G‐34T), located in the 5′ UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G‐34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5′ UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN 2 A promoter appear to have a limited role in predisposition to melanoma. Genes Chromosomes Cancer 28:45–57, 2000. © 2000 Wiley‐Liss, Inc.