Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study

Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy-related (ATG) genes have been investigated in relation to melanoma progression. We examined five single-nucleotide polymorphisms (SNPs) in three ATG genes (ATG5; ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27-0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11-1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12-3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05-0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21-0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34-0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression

Associations of Cumulative Sun Exposure and Phenotypic Characteristics with Histologic Solar Elastosis

Solar elastosis adjacent to melanomas in histologic sections is regarded as an indicator of sun exposure although the associations of ultraviolet (UV) exposure and phenotype with solar elastosis are yet to be fully explored

Copy number variations in alternative splicing gene networks impact lifespan.

Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P=3.33×10(-8)-1.6×10(-2) unadjusted), while only one duplication was enriched in the geriatric cohort (P=6.3×10(-4)). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P=5.16×10(-5)-4.26×10(-2)) in the replication cohort. Three deletions and four duplications were significant combined (combined P=3.7×10(-4)-3.9×10(-2)). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing (P=0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan

Manhattan Plot of SNP based CNV Statistics. (A)Deletions and (B)Duplications.

<p>Manhattan Plot of SNP based CNV Statistics. (A)Deletions and (B)Duplications.</p

Discovery and Replication Case:Control Sample Sets.

<p>Contributing project totals in discovery and replication phases. The totals represent the number of high quality datasets derived from samples.</p

Representative Interactions of the Lifespan Longevity Associated Genes Identified.

<p>Gene-gene interactions of independently significant loci. Additional genes implicated by interacting with genes in significantly associated longevity loci. Alternative splicing gene function annotation enrichment of significant loci suggests diverse genetic perturbation with a common biological role. Extension of this functional category to other genes annotated by functional studies with interactions to associated genes implicates potential for screening diverse etiology.</p

CNVs Enriched in Pediatric Individuals.

*<p>Gene not overlapped so closest proximal gene annotated. Gene delimiters were defined based on UCSC genes table reference including exons and introns. Any direct overlap of any segment of the gene delimiters is considered a hit such that complete overlap of the gene is not required. Combined p-values were calculated using Fisher’s method.</p

Principle Components Analysis of Pediatric and Geriatric Cohorts.

<p>Discovery U.S. Pediatric vs. Icelandic Geriatric A) Principle components (PC) 1 vs. 2 shows distinct clusters likely due to sporadic differential profiles of a specific subset of SNPs between arrays. Since CNV calling is based on multiple neighboring SNPs and differential clustering SNPs are randomly distributed, CNV discovery should not experience significant bias. B) PC2 vs. 3 representing population structure showing some overlap of pediatric and geriatric cohorts C) SNP genotype allele frequency differences genome wide showing close correlation. Replication U.S. Pediatric vs. U.S. Geriatric D) Replication of U.S. pediatric and U.S. geriatric PC1 vs. PC2 showing high overlap unlike panel A U.S. pediatric and Icelandic geriatric E) Geriatric replication cohort in isolation for clarity F) Population structure of pediatric subjects with significantly associated risk CNVs for short lifespan showing broad normal distribution minimizing test statistic inflation for rare variants opposed to tight clustering(37) G) Pediatric replication cohort in isolation for clarity.</p

CNVs Enriched in Geriatric Individuals.

<p>CNVs Enriched in Geriatric Individuals.</p