Missense and Intronic Variants in HNF1A Affect Prostate Cancer Aggressiveness in Patients with Biochemical Recurrence

TL;DR

This study finds that specific genetic variants in the HNF1A gene are linked to more aggressive prostate cancer, especially in patients who experience biochemical recurrence.

Contribution

The study identifies novel associations between HNF1A genetic variants and prostate cancer aggressiveness in patients with biochemical recurrence.

Findings

HNF1A SNPs rs735396, rs2464196, and rs1169288 are associated with higher Gleason grades in prostate cancer patients.

HNF1A expression is elevated in cancerous prostate tissues and correlates with more advanced cancer stages and metastasis.

The identified SNPs may influence HNF1A expression and cancer aggressiveness, particularly in patients with biochemical recurrence.

Abstract

Prostate cancer (PCa) is a genetically and phenotypically heterogeneous disease, and further advancements in PCa biomarker discovery are urgently required. Hepatocyte nuclear factor 1 A (HNF1A), a transcription factor, plays a critical role in PCa progression after biochemical recurrence (BCR). However, studies investigating the impact of HNF1A genetic variants on PCa are scarce. Therefore, in this study, we explored the associations of HNF1A single-nucleotide polymorphisms (SNPs) with susceptibility to BCR in PCa and its clinicopathological development. Two nonsynonymous (missense) SNPs [rs2464196 (S487N) and rs1169288 (I27L)] and two intronic SNPs [rs1169286 and rs735396] were analyzed using a TaqMan allelic discrimination assay for genotyping in a cohort of 690 Taiwanese patients with PCa. The results demonstrated that patients with PCa carrying the HNF1A rs735396 (TC+CC), rs2464196 (GA+AA), or rs1169288 (AC+CC) had a higher risk of developing tumors with higher pathological Gleason grades (3-5). These associations were particularly evident in the BCR subpopulation. Moreover, analysis of data from The Cancer Genome Atlas revealed that HNF1A expression was higher in PCa tissues than in normal tissues. Moreover, higher HNF1A expression was correlated with higher Gleason scores, more advanced pathological T stages, and metastasis. Taken together, our findings indicated that elevated HNF1A expression promotes PCa progression and that the missense SNPs rs2464196 and rs1169288, as well as the intronic SNP rs735396, may influence HNF1A expression, thereby influencing PCa aggressiveness, particularly in patients with BCR.

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