An Exploratory Analysis of Tumor Site- and Sex-Specific Associations of SNPs of LncRNA CCAT1, CCAT2, H19, HOTAIR, and PTCSC3 in Colorectal Lesions: A Hungarian Case–Control Study

<b>Background:</b> Colorectal cancer is a major public health burden in Hungary, with one of the highest incidence and mortality rates in Europe. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumorigenesis, but population-specific genetic associations remain understudied. This study aimed to investigate whether single-nucleotide polymorphisms (SNPs) in lncRNA genes are associated with colorectal cancer susceptibility, with attention to tumor site- and sex-specific effects. <b>Methods:</b> We conducted an exploratory case-control study involving 91 Hungarian participants (38 patients with colorectal lesions and 53 controls). Genotyping of six SNPs located in HOTAIR, PTCSC3, H19, CCAT1, and CCAT2 was performed using TaqMan-based qPCR. Associations were tested using allele frequency analysis, different genotype models (dominant, recessive, additive), and binary logistic regression, including stratified analyses by tumor subtype and sex. <b>Results:</b> While no significant associations were found in the unadjusted overall case-control comparisons, logistic regression including sex revealed that HOTAIR rs12826786 and rs7958904 were significantly associated with a reduced risk of colorectal lesions, particularly in females (<i>p</i> = 0.022 and <i>p</i> = 0.043). Analyses by tumor localization revealed that H19 rs2839698 and PTCSC3 rs944289 were more frequent in colon than in rectal tumors (<i>p</i> = 0.017 and <i>p</i> = 0.035) and were associated with a reduced risk of rectal tumors (OR = 0.18 and OR = 0.20), suggesting that these variants may influence tumor site rather than overall susceptibility. None of the results remained significant after Bonferroni correction. <b>Conclusions:</b> Our findings suggest that these selected lncRNA-related SNPs may contribute to colorectal cancer risk in a sex- and site-specific manner. These preliminary results warrant further validation in larger, independent cohorts and functional studies.