Germline alterations of the cyclin dependent kinase

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Unformatted text preview: clin-dependent kinase inhibitor 2A (CDKN2A) are important genetic factors in familial predisposition to melanoma. Activating mutations of the NRAS proto-oncogene are among the most common somatic genetic alterations in cutaneous malignant melanomas. We performed a study in which NRAS mutations in melanomas from 25 patients in six Swedish melanoma-prone families carrying germline CDKN2A mutations were compared with NRAS mutations in melanomas from patients with sporadic melanomas. Five families carried the Swedish founder 113insR germline mutation in exon 2 of CDKN2A, and one family carried a P48L germline mutation in exon 1 of CDKN2A. Genomic DNA was extracted from biopsy samples including primary melanomas, metastatic melanomas, and dysplastic nevi, using laser capture microscopy techniques. DNA was also extracted from 10 biopsy samples from patients with sporadic melanomas. NRAS was analyzed using polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequence analysis. Activating mutations in NRAS codon 61, all of which were either Q61K or Q61R mutations, were found in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10) of sporadic melanomas (P<.001) from patients with no family history of melanoma. Multiple activating NRAS mutations were detected in tumor cells from different regions of individual primary melanomas in nine patients. The same NRAS mutations that were present in the primary tumors were also detected in all metastases 28 from these patients, indicating a clonal relationship between melanoma cells in primary and metastatic melanoma tumors. However, additional NRAS mutations at sites other than at codon 61 were also present in these metastases. The presence of NRAS mutations in dysplastic nevi and in an in situ melanoma tumor suggest that NRAS mutations may be early events in the development of melanoma in individuals with germline CDKN2A mutations. In contrast, no NRAS mutations were detected in common nevi and normal skin tissue biopsies. We conclude that the high fre...
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