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Background/Objectives: The KRAS rs61764370 T>G single-nucleotide polymorphism (SNP), located in a let-7 microRNA binding site within the 3′ untranslated region (3′UTR) of the KRAS gene, may modulate tumor aggressiveness by altering post-transcriptional gene regulation. This study evaluated its association with adverse histopathological features in colorectal cancer (CRC). Methods: A preliminary study on 83 CRC patients carrying either the TT (wild-type, n = 64) or TG (heterozygous, n = 19) genotype was analyzed. Clinicopathological variables included patient sex, tumor location, American Joint Committee on Cancer (AJCC) staging system, histological grade, perineural invasion (PNI), and lymphovascular invasion (LVI). A composite “tumor aggressiveness” score was defined based on the presence of Grade 3 differentiation, LVI, and/or PNI. Group comparisons were performed using the Chi-square test or Fisher’s exact test, as appropriate. Results: No statistically significant differences were observed in sex (p = 0.689), tumor location (p = 0.781), or stage at diagnosis (p = 0.812). Poorly differentiated tumors (Grade 3) were present in 20.3% of TT patients and absent in TG carriers (p = 0.06), while low-grade tumors (Grade 1) were more prevalent among TG patients (47.4%) compared to TT (29.7%). The composite high-aggressiveness score was lower in TG (36.8%) than in TT (48.4%), while co-occurrence of PNI and LVI was similar in both groups (~26%). Conclusions: Although no significant associations were identified, TG carriers showed a tendency toward lower-grade, less aggressive tumors. Given the limited sample size, these findings should be interpreted with caution, necessitating larger cohorts in order to validate results.

Background Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3 ′ untranslated region (3 ′ UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1 st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/− cetuximab. Methods The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314). Results LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) ( P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16). Conclusions The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1 st line Nordic FLOX +/− cetuximab.

There is a small but growing body of literature regarding the predictive utility of a Let‐7 microRNA‐binding‐site polymorphism in the 3′‐untranslated region (UTR) of KRAS (KRAS‐LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta‐analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let‐7 microRNA‐binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse‐variance weight to calculate fixed‐ and random‐effects summary estimates and corresponding 95% CIs for overall and progression‐free survival. We did not observe any significant association between overall or progression‐free survival, neither when considering all colorectal cancer patients nor for subgroup analyses (metastatic, anti‐EGFR [epidermal growth factor receptor] treatment, or KRAS wild type). There was substantial heterogeneity across studies, overall and among subgroups analyzed. We have found no clear evidence to support an association between the KRAS‐LCS6 genotype and overall or progression‐free survival among colorectal cancer patients, even after conducting subgroup analyses by stage and anti‐EGFR treatment status. This information helps to clarify the confusing body of literature regarding the clinical implications of the KRAS‐LCS6 genetic variant on colorectal cancer outcomes, indicating that it should not be used at the present time to personalize therapeutic strategies (PROSPERO registration number: CRD42013005325). We conducted a meta‐analysis of the prognostic significance of the LCS6 let‐7‐binding‐site polymorphism in the 3′UTR of KRAS. We did not find any evidence of association with overall or disease‐free survival, or by stage at diagnosis or treatment regimen.

Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3'untranslated region (3'UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/- cetuximab. The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314). LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16). The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/- cetuximab.

There is a small but growing body of literature regarding the predictive utility of a Let-7 microRNA-binding-site polymorphism in the 3'-untranslated region (UTR) of KRAS (KRAS-LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta-analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let-7 microRNA-binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse-variance weight to calculate fixed- and random-effects summary estimates and corresponding 95% CIs for overall and progression-free survival. We did not observe any significant association between overall or progression-free survival, neither when considering all colorectal cancer patients nor for subgroup analyses (metastatic, anti-EGFR [epidermal growth factor receptor] treatment, or KRAS wild type). There was substantial heterogeneity across studies, overall and among subgroups analyzed. We have found no clear evidence to support an association between the KRAS-LCS6 genotype and overall or progression-free survival among colorectal cancer patients, even after conducting subgroup analyses by stage and anti-EGFR treatment status. This information helps to clarify the confusing body of literature regarding the clinical implications of the KRAS-LCS6 genetic variant on colorectal cancer outcomes, indicating that it should not be used at the present time to personalize therapeutic strategies (PROSPERO registration number: CRD42013005325).