Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

Abstract

In rectal cancer, a pathologic complete response (pCR) to pre-operative treatment is a favourable prognostic marker, but is reported in a minority of the patients. We aimed at identifying microRNA-related host genetic polymorphisms predictive of pCR.A panel of 114 microRNA-related tagging polymorphisms was selected and analyzed on 265 locally advanced rectal cancer patients treated with neoadjuvant chemo-radiotherapy. Patients were stratified in two subgroups according to the radiotherapy dose (50.4Gy for 202 patients, 55.0Gy for 78 patients). Interactions among genetic and clinical-pathological variants were investigated by recursive partitioning analysis.Only polymorphisms with a consistent significant effect in the two subgroups of patients were selected as predictive markers of pCR. The results were validated by bootstrap analysis. SMAD3-rs744910, SMAD3-rs745103, and TRBP-rs6088619 were associated to an increased chance of pCR (p=0.0153, p=0.0471, p=0.0125). DROSHA-rs10719 and SMAD3-rs17228212 had an opposite detrimental effect on pathological tumour response (p=0.0274, p=0.0049). Recursive partitioning analysis highlighted that a longer interval time between the end of radiotherapy and surgery increases the chance of pCR in patients with a specific combination of SMAD3-rs744910 and TRBP-rs6088619 genotypes.This study demonstrated that microRNA-related host genetic polymorphisms can predict pCR to neo-adjuvant chemo-radiotherapy, and could be used to personalize the interval time between the end of radiotherapy and surgery.

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…The genes SMAD family member 3 ( SMAD3 ), trans-activation-responsive RNA-binding protein ( TRBP ) and double-stranded RNA-specific endoribonuclease ( DROSHA ) play a crucial roles in microRNA processing [137] and SNPs in these genes (rs745103, rs744910 and rs1722821 for SMAD3 ; rs6088619 for TRBP ; and rs10719 for DROSHA ) were significantly associated with nCRT response in 265 rectal cancer patients [138]. The occurrence of SNPs located in miRNA target sites may affect interaction of miRNA and target genes and may modulate target gene expression, potentially affecting risk and clinical outcome of CRC.…”

Genetic variants of microRNA processing genes and risk of non‐syndromic orofacial clefts

“…DROSHA /rs10719 was previously found to be associated with different kinds of cancers (Dreussi et al., ; Khan et al., ; Yuan et al., ). In addition, based on SNPinfo database (http://snpinfo.niehs.nih.gov), rs10719 A allele and G allele was also associated with different miRNAs.…”

The Role of Micro-RNAs and Circulating Tumor Markers as Predictors of Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer

“…Few studies focused on the involvement of miR-SNPs in LARC [ 121 , 122 , 123 ]. For instance, the prognostic role of the SNP rs4919510, that is characterized by the guanine to cytosine (G > C) base substitution in the sequence of the mature miRNA-608, has been explored in LARC patients subjected to neodjuvant capecitabine and oxaliplatin (CAPOX) treatment followed by CRT, surgery, or to adjuvant CAPOX ± cetuximab treatment [ 121 ].…”

“…In another study, 265 Caucasian LARC patients (divided in two subgroups depending on the radiation dose) subjected to neoadjuvant CRT based on 5-FU were screened for a panel of 114 miR-SNPs [ 123 ]. A total of five SNPs were identified in miRNAs target genes.…”

“…In detail, two SNPs in SMAD Family Member 3 (SMAD3) (rs744910 and rs745103) and one SNP in transactivation response element RNA-binding protein (TRBP) (rs6088619) were predictive of pCR. In contrast, the SNPs rs10719 (in Drosha) and rs17228212 (in SMAD3) had an unfavorable chance of pCR [ 123 ].…”