Abstract 6217: Methylation-derived inflammation phenotypes and anal cancer risk among men with HIV

Abstract Introduction: Inflammation is a hallmark of cancer. DNA methylation (DNAm) derived immune cell type proportions and circulating inflammation-related protein markers are precise measures of inflammatory phenotypes. We investigated the associations of DNAm-derived inflammation-related phenotypes with risks of anal cancer and precancer (high-grade squamous intraepithelial lesions, HSIL) among men with HIV. Method: We matched 22 anal cancer cases to 37 controls with normal anal epithelium and 54 HSIL to 90 controls using propensity score methods. DNAm data were profiled by MethylationEPIC v2.0 array on the pre-diagnostic blood biospecimens and processed by R minfi and ChAMP packages. Immune cell composition, including 4 myeloid (neutrophils, eosinophils, basophils and monocytes) and 8 lymphoid cell sub-lineages (B lymphocytes naïve (Bnv), B lymphocytes memory [Bmem], T helper lymphocytes naïve [CD4nv], T helper lymphocytes memory [CD4mem], T regulatory cells [Treg], T cytotoxic lymphocytes naïve [CD8nv], T cytotoxic lymphocytes memory [CD8mem], and natural killer lymphocytes) were estimated among normalized DNA methylation β values using a reference-based deconvolution algorithm. Proportions of these 12 major immune cell types were estimated to be 100%. Ratios of CD4nv/CD4mem, CD8nv/CD8mem, Bnv/Bmem, CD8/Treg, and neutrophil/lymphocyte were computed. Additionally, 47 DNAm-predicted circulating inflammation-related protein levels were calculated using well-established prediction models. Conditional logistic regression models were built to estimate odds ratios (OR) and 95% confidence intervals (CI) on per standard deviation increase in inflammation phenotypes adjusting for cell type heterogeneities. Results: Higher CD4nv/CD4mem (OR=2.70, 95%CI:1.09-6.70) and lower CD8/Treg (OR=0.56, 95%CI:0.31-0.99) was positively associated with anal cancer risk at nominal P < 0.05. Higher Bnv/Bmem (OR=1.47, 95%CI:1.02-2.12) was linked to increased HSIL risk at nominal P < 0.05. Elevated levels of DNAm-derived circulating protein MMP9 (OR=1.86, 95%CI: 1.20-2.88), C5 (OR=1.78, 95%CI: 1.23-2.57), B2M (OR=1.75, 95%CI:1.16-2.65), CRP (OR=2.39, 95%CI:1.32-4.33), MMP12 (OR=1.66, 95%CI:1.15-2.41), CCL11(OR=1.66, 95%CI:1.15-2.38) , TNFRSF1B (OR=1.85, 95%CI:1.20-2.87), HGF (OR=2.10, 95%CI:1.32-3.35), TGFA (OR=2.38, 95%CI:1.31-4.35), VEGFA (OR=1.82, 95%CI:1.21-2.72), CCL17 (OR=1.93, 95%CI:1.26-2.95); and decreased levels of ADAMTS13 (OR=0.47, 95%CI:0.28-0.78) were associated with increased risk of anal cancer and HSIL (combined analysis) compared to controls at false discovery rate (FDR) <5%. No significant associations were observed when comparing cancers with controls or comparing HSIL with controls, separately at FDR<5%. Discussion: Our findings suggest that inflammation plays a role in anal carcinogenesis. Future research is warranted to validate our results. Citation Format: Shuai Xu, Bryan E. Shepherd, Tebeb Gebretsadik, Anna Junkins, Jirong Long, Qiuyin Cai, Staci L. Sudenga. Methylation-derived inflammation phenotypes and anal cancer risk among men with HIV [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6217.