In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 867-867
Abstract:
Up to 10% of all melanoma patients show a family history of disease. One main predisposing gene for familial melanoma development is CDKN2A, a tumor suppressor gene that encodes two distinct proteins, p16INK4A and p14ARF. CDKN2A germline mutations have been found in 20-40% of melanoma-prone families. So far, BRAF and NRAS are the most frequently altered oncogenes described in cutaneous melanoma. To date, little is known about the somatic changes that occur in familial melanoma. The aim of this study was to determine the prevalence of BRAF and NRAS somatic mutations in familial melanomas and to evaluate the associations between these mutations and clinicopathological factors. The study was performed as a collaboration within GenoMEL (The Melanoma Genetics Consortium). A total of 135 primary familial cutaneous melanomas (88 tumors from CDKN2A mutation-carriers and 47 from CDKN2A non-carriers) were investigated. Paraffin-blocks of tumors were collected from 8 GenoMEL centers in Australia, Italy, Latvia, the Netherlands, Spain, Sweden, and UK. Tumor cells were isolated by laser capture microdissection and mutation screening (BRAF exon 15 and NRAS exon 3) was performed by direct sequencing. Mutation analysis revealed BRAF and NRAS mutations in 41.6% and 11.4% of tumors, respectively. In no case were BRAF and NRAS mutations found to coexist in the same tumor. There was no difference in BRAF mutation frequency between tumors from patients with CDKN2A alterations and tumors from patients wild-type for CDKN2A (41.0% vs. 42.9%). Similarly, the frequency of NRAS mutations did not differ markedly when tumors from CDKN2A mutation-carriers and non-carriers were compared (9.0% vs. 15.6%). There was also no difference in the frequency of BRAF mutations between tumors with CDKN2A mutations disrupting both p16INK4A and p14ARF and tumors with CDKN2A mutations affecting p16INK4A only (40.6% vs. 36.4%). When tumors with different CDKN2A founder mutations were compared, BRAF mutations were seen in 50.0%, 45.8%, 37.5% and 35.0% of p.M53I, p.R112_L113insR, p.G101W and c.225_243del19 altered tumors, respectively. NRAS mutations were observed in 14.3% 12.5% and 10.5% of p.R112_L113insR, p.M53I and c.225_243del19 altered tumors, respectively, whereas no NRAS mutations were seen in tumors with the p.G101W founder mutation. Patients with BRAF-mutated tumors had a significantly lower median age at diagnosis compared to patients with NRAS-mutated or BRAF/NRAS wild-type tumors (43.5, 54 and 51.5 years, respectively). Moreover, melanomas with mutated BRAF or NRAS were thicker than BRAF/NRAS wild-type cases (median thickness 1.0, 1.4 and 0.7mm, respectively). Our results suggest a role for the BRAF and NRAS oncogenes in familial melanoma. Somatic changes of these genes occur in tumors from both CDKN2A mutation carriers and non-carriers. Presence of BRAF or NRAS mutations associated with patient and tumor characteristics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2011-867
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-867
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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