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Dear Editor, We have previously shown that the functional melanoma risk variant rs12203592 in the I IRF4 i gene (interferon regulatory factor-4) was associated with increased Breslow thickness, an important prognostic indicator for melanoma.[1] In line with this, a recent study found evidence for an association between the minor T allele of this single-nucleotide polymorphism (SNP) and melanoma-specific survival in patients from two European hospitals.[2] We therefore sought to extend our previous work and replicate these hospital-based findings by investigating the association of rs12203592 with melanoma-specific survival, overall and by anatomical site. A mediation analysis found that 70-2% of the observed association between rs12203592*T and melanoma-specific survival was mediated through Breslow thickness, with significant natural indirect effects identified (HR 1-13, 95% CI 1-06-1-20; I P i < 0-001). Our results suggest that I IRF4 i rs12203592 is associated with poorer melanoma-specific survival, largely mediated through Breslow thickness, reinforcing our previous findings related to rs12203592*T and tumour thickness.[1] This variant's adverse effect on survival may occur through its functional effect on I IRF4 i expression. [Extracted from the article]

Focuses on a study of mutation related prostate cancer among Ashkenazi Israelis. Association of the tumors biologically more aggressive disease; Implications for male carriers of Ashkenazi founder mutations; Association of the mutations with pathological or clinical features.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2[sup *]1906G→C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P = .042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P = .033 ). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria. [ABSTRACT FROM AUTHOR]