Contribution of Germline Mutations inBRCA2,P16^INK4A,P14^ARFandP15to Uveal Melanoma

Abstract

PURPOSE.Reports suggest that a subset of uveal melanoma is familial. The association of uveal melanoma with breast and ovarian cancer and the increased risk in BRCA2-linked families implicates germline BRCA2 mutations as the cause of a subset of uveal melanomas. Similarly, the association between cutaneous and uveal melanomas in some families, coupled with the high frequency of somatic deletions of the INK4A-ARF locus in uveal melanomas, strongly suggests that mutations in P16 INK4Aand P15 account for a proportion of uveal melanomas. METHODS. To examine this proposition, a systematically ascertained series of 385 patients with uveal melanoma were screened for germline mutations in BRCA2, P16INK4A , P14 ARF , and P15. RESULTS. One patient was found to harbor a Gly35Ala substitution in exon 1␣ of P16 INK4A , which has previously been reported to be pathogenic. No mutations were detected in P14 ARF or P15. None of the patients harbored germline nucleotide changes that lead to truncation or that create or disrupt consensus splice sites of BRCA2 or missense variants with clear pathogenic potential. CONCLUSIONS. These findings suggest that less than 2% of cases of uveal melanoma can be ascribed to germline mutations in BRCA2, P16INK4A , P14 ARF , or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma. (Invest Ophthalmol Vis Sci. 2003;44:458 -462)

CDKN2A as a uveal and cutaneous melanoma susceptibility gene

“…Taken together, these observations suggest that the G67S mutation alters both CDKN2A and ARF functions, and is thus instrumental in melanoma predisposition. Our finding of a CDKN2A germline mutation in a "mixed" UM and CM family is consistent with the very recent description of a CDKN2A germline mutation in a patient affected by UM without a family history of either CM or UM (Hearle et al, 2003).…”

INK4a-ARF alterations in Barrett?s epithelium, intraepithelial neoplasia and Barrett?s adenocarcinoma

“…The findings of the present study indicate that aberrant methylation is a major mechanism of selective inactivation of the INK4a-ARF locus in patients with Barrett's neoplasia. Specific mutations of p16 INK4a and p14 ARF are rare and have been described in very few patients with glioma, pancreatic cancer and melanoma [3,20,24,37]. Sole p14 ARF mutations or homozygous deletions that spare the remainder p16 INK4a have been described only in a melanoma-cell line and glioma xenograft [23].…”

Absence of founder BRCA1 and BRCA2 mutations in coetaneous malignant melanoma patients of Ashkenazi origin

“…A positive study of 140 Ashkenazi patients with ocular melanoma suggested an OR of approximately 4 in association with the 6174delT BRCA2 mutation [13]. This was contradicted by a recent study of 385 patients with uveal melanoma, where no pathogenic BRCA2 mutation could be detected [14]. Landi et al [15] also failed to detect any mutations in the coding region of BRCA2 gene in 55 Italian families prone to melanoma and having at least two relatives with melanoma.…”