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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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