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Genetic Differences May Exist Between Single, Multiple Keratinocyte Cancer Cases

NEW YORK (GenomeWeb) – An international team has taken steps to determine whether both genetic and environment factors might contribute to the risk of developing not just one, but multiple tumors that arise from keratinocyte cells in the skin's epidermal layer, such as basal cell carcinoma or squamous cell carcinoma.

As they reported online yesterday in PLOS One, researchers from the Netherlands and the US did a genome-wide association study involving thousands of individuals with either single or multiple keratinocyte cancers, following by replication analyses in hundreds more individuals from each group. Their search did not lead to SNPs with strong ties to multiple keratinocyte cancer risk, perhaps reflecting environmental contributions to the disease, a modest sample size, and/or differences in the criteria used to define multiple cancers between cohorts.

Even so, the team saw several suspicious SNPs in its GWAS and meta-analyses. And when it tested a collection of variants implicated in basal cell carcinoma in the past, at least one SNP showed significant ties to multiple keratinocyte cancer risk.

"Whether the differential risk between patients with [multiple keratinocyte cancers] and [single keratinocyte cancers] is due to genes or mostly due to environmental factors, or an interaction of genes and environmental factors remains to be elucidated," the authors wrote.

Prior studies suggest that multiple keratinocyte cancers are particularly common in those with pale hair and skin, in men, and/or individuals exposed to ultraviolet light. But there have also been hints that individuals who experience one bout of basal cell carcinoma or squamous cell carcinoma might have slightly different genetic risk factors than those with two or more such cancer, the researchers explained, leading them to search for specific SNPs with ties to multiple keratinocyte cancer risk.

The team turned to data from the Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study and the Framingham Heart Study to identify 1,950 single keratinocyte cancer cases and 1,666 cases involving multiple keratinocyte cancers.

When the researchers compared patterns at roughly 8 million SNP genotyped or imputed SNPs in individuals with one or multiple keratinocyte cancers, they focused in on 40 SNPs for subsequent analyses — many of them in linkage disequilibrium with one another.

But the associations with multiple keratinocyte cancer did not hold when they tested these SNPs in another 872 single keratinocyte cancer cases and 573 multiple keratinocyte cancer cases. Their meta-analysis, using data from the replication and discovery datasets, revealed only suggestive ties to multiple keratinocyte cancer.

Half a dozen SNPs previously associated with basal cell carcinoma risk did turn up with enhanced frequency in individuals with multiple keratinocyte cancers, the team reported, though only a single SNP in the MC1R gene remained significant after further analysis.

The authors noted that further insights into the potential heritability and risk of multiple keratinocyte cancer may come from larger studies and studies focused on rare, rather than common, genetic variants.

"Although [rare] variants may not be clinically relevant to predict disease risk, they may reveal new pathways predisposing to [multiple keratinocyte cancers] and new targets for drug discovery," they wrote.

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