Schneiderova Michaela, Naccarati Alessio, Pardini Barbara, Rosa Fabio, Gaetano Cornelia Di, Jiraskova Katerina, Opattova Alena, Levy Miroslav, Veskrna Karel, Veskrnova Veronika, Buchler Tomas, Landi Stefano, Vodicka Pavel, Vymetalkova Veronika
Department of Surgery, General University Hospital in Prague, Prague 12800, Czech Republic.
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic.
Mutagenesis. 2017 Oct 17;32(5):533-542. doi: 10.1093/mutage/gex026.
According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome. Eight miRSNPs (rs1804191, rs397768, rs41116 in APC; rs1137918, s227091, rs4585 in ATM; rs712, rs1137282, rs61764370 in KRAS; rs8674 in PARP1 and rs16950113 in SMAD7) were tested for their association with CRC risk in a case-control study (1111 cases and 1469 healthy controls). The role of these miRSNPs was also investigated in relation to clinical outcome on a subset of patients with complete follow-up. rs8679 within PARP1 was associated with CRC risk and patients' survival. In the dominant model, carriers of at least one C allele were at a decreased risk of cancer (P = 0.05). The CC genotype in rs8679 was also associated with an increased risk of recurrence/progression in patients that received 5-FU-based chemotherapy (log-rank test P = 0.03). Carriers of the homozygous variant genotype TT for rs712 in KRAS gene were associated with a decreased risk of rectal cancer (odds ratio (OR) = 0.65, 95% confidence intervals (CI) 0.43-1.00, P = 0.05) while individuals with colon cancer carrying the heterozygous GT genotype showed a longer overall survival (OS) (P = 0.04). We provide the first evidence that variations in potential miRNA-binding target sites in the 3' UTR of PARP1 gene may modulate CRC risk and prognosis after therapy. Further studies are needed to replicate our finding and assess miRSNPs as predictive biomarkers in independent populations.
根据Vogelstein的结直肠癌发生模型，高外显率基因的遗传变异可能参与结直肠癌（CRC）的发病机制。同样，微小RNA（miRNA）的功能异常和/或表达改变在CRC中也经常出现。在这种情况下，miRNA结合位点多态性（miRSNPs）可能影响miRNA/靶基因相互作用，导致mRNA/蛋白质表达差异，并增加对常见疾病的易感性。为了探究这一现象，我们挖掘了已知在CRC中频繁突变的基因的3'非翻译区（3'UTRs），以寻找miRSNPs，并测试它们与CRC风险和临床结局的关联。在一项病例对照研究（1111例病例和1469名健康对照）中，对8个miRSNPs（APC基因中的rs1804191、rs397768、rs41116；ATM基因中的rs1137918、s227091、rs4585；KRAS基因中的rs712、rs1137282、rs61764370；PARP1基因中的rs8674和SMAD7基因中的rs16950113）与CRC风险的关联进行了测试。还在一组有完整随访的患者中研究了这些miRSNPs与临床结局的关系。PARP1基因内的rs8679与CRC风险和患者生存相关。在显性模型中，至少携带一个C等位基因的携带者患癌风险降低（P = \alpha05）。rs8679的CC基因型也与接受基于5-氟尿嘧啶化疗的患者复发/进展风险增加相关（对数秩检验P = \alpha03）。KRAS基因中rs712的纯合变异基因型TT携带者患直肠癌的风险降低（优势比（OR） = \alpha65，95%置信区间（CI）0.43 - 1.00，P = \alpha05），而携带杂合GT基因型的结肠癌患者总生存期（OS）更长（P = \alpha04）。我们提供了首个证据，表明PARP1基因3'UTR中潜在miRNA结合靶位点的变异可能调节CRC风险和治疗后的预后。需要进一步研究来重复我们的发现，并在独立人群中评估miRSNPs作为预测生物标志物的作用。
