A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.

Analysis of Meis2 knockout mice reveals Sonic hedgehog-mediated patterning of the cochlear duct.

BACKGROUND: The mechanisms underlying the formation of complex structures such as during the outgrowth of the cochlear duct are still poorly understood. RESULTS: We have analyzed the morphological and molecular changes associated with cochlear development in mouse mutants for the transcription factor Meis2, which show defective coiling of the cochlea. These morphological abnormalities were accompanied by the formation of ectopic and extra rows of sensory hair cells. Gene profiling of otic vesicles from Meis2 mutants revealed a dysregulation of genes that are potentially involved in Sonic hedgehog (Shh)-mediated patterning of the cochlear duct. Like in Shh mutants, Meis2 defective mice showed a loss of genes that are expressed in the apical part of the cochlear duct. CONCLUSIONS: Taken together, these data reveal that the loss of Meis2 leads to a phenotype that resembles Shh mutants, suggesting that Meis2 is instrumental for cochlear Shh signaling. The modulation of the same subset of genes provides an interesting insight into which Shh responsive genes are essential for outgrowth and patterning of the cochlear duct.

The association of diet-dependent acid load with colorectal cancer risk: a case-control study in Korea.

Acid-base disequilibrium is a contributor to cancer development because it affects molecular activities such as insulin-like growth factor 1 levels and adiponectin production. However, evidence of an association of diet-induced acid-base imbalance with colorectal cancer (CRC) is limited. We examined whether colorectal carcinogenesis is attributable to a diet with a high acid load. We recruited a total of 923 CRC cases and 1846 controls at the National Cancer Center in Korea for inclusion in a case-control study. We collected information on nutrient intake and specific clinical parameters of CRC by using a semiquantitative FFQ and medical records, respectively. Potential renal acid load (PRAL) and net endogenous acid production (NEAP) were used to estimate diet-dependent acid load. We used an unconditional logistic regression model to analyse the association. Dietary acid load scores had a positive association with the odds of CRC (OR = 2·31 (95 % CI 1·79, 2·99) and OR = 2·14 (95 % CI 1·66, 2·76) for PRAL and NEAP, respectively, Pfor trend < 0·001). A stronger positive association was observed for females (OR = 3·09, 95 % CI 1·93, 4·94) than for males (OR = 1·71, 95 % CI 1·27, 2·31). Furthermore, acidogenic diets appeared to affect rectal cancer more strongly than colon cancer in females. Our study contributes to reinforcing epidemiological evidence regarding a detrimental effect of acidogenic diets on colorectal carcinogenesis. Thus, it is important to pay attention to the balance of acidogenic (e.g. poultry and red meat) and alkalinogenic foods (e.g. fruits and vegetables) in CRC prevention, especially for females.

The interaction effect of dietary selenium intake and the IL10 rs1800871 polymorphism on the risk of colorectal cancer: a case-control study in Korea.

The importance of Se in human health has received much attention due to its antioxidant properties when it is consumed at an appropriate level. However, the existing evidence is limited to obtain an effective conclusion for colorectal cancer (CRC). Notably, an adequate intake of Se was reported for Koreans. Furthermore, cytokine secretion and immune function may be affected by dietary Se. Our study aimed to explore whether Se potentially reduces CRC risk and whether the IL10 rs1800871 polymorphism has an effect on this association. We designed a case-control study with 1420 cases and 2840 controls. A semi-quantitative FFQ was used to obtain information on Se intake. We determined IL10 rs1800871 through genetic analysis. Different models were developed to explore Se intake related to CRC risk by calculating OR and 95 % CI using unconditional logistic regression. A reduced risk of CRC was found as Se intake increased, with an OR (95 % CI) of 0·44 (0·35, 0·55) (Pfor trend < 0·001). However, this association seems to be allele-specific and only present among risk variant allele carriers (GA/GG) with a significant interaction between dietary Se and IL10 rs1800871 (Pfor interaction = 0·043). We emphasised that a reduction in CRC risk is associated with appropriate Se intake. However, the IL10 rs1800871 polymorphism has an impact on this reduction, with a greater effect on variant allele carriers. These findings suggest the importance of considering an individual's genetic characteristics when developing nutritional strategies for CRC prevention.

Are sporadic colorectal cancers in young patients distinct from those in elderly patients?

AIM: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. METHOD: In this cross-sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. RESULTS: The median age at diagnosis was 37 years in the yCRC group (range 33.0-39.2 years) and 76 years in the eCRC group (range 72.0-79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3-year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer-specific survival. CONCLUSION: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. CLINICAL TRIAL REGISTRATION NUMBER: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609).

Relationship Between Aspirin Use and Site-Specific Colorectal Cancer Risk Among Individuals With Metabolic Comorbidity.

BACKGROUND: The relationship between aspirin usage and the risk of colorectal cancer (CRC) among individuals with both hypertension (HTN) and diabetes mellitus (DM) remains unclear. This study aims to explore the impact of aspirin use on the site-specific CRC risk in patients with metabolic comorbidity. METHODS: A case-control study was conducted among 1,331 CRC patients and 2,771 controls recruited from the Nation Cancer Center in Korea. Multinomial logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between aspirin use, metabolic disease status, and site-specific CRC risk. RESULTS: Among the 4,102 participants, 1,191 individuals had neither HTN nor DM, 2,044 were diagnosed with HTN, 203 with DM, and 664 presented with HTN and DM comorbidity. An increasing number of HTN and DM was associated with an increased risk of overall CRC (HTN or DM: OR, 1.70; 95% CI, 1.39-2.07; HTN and DM: OR, 8.43; 95% CI, 6.37-11.16), while aspirin use was associated with a decreased risk of overall CRC (OR, 0.31; 95% CI, 0.21-0.46). These results remained consistent across anatomical sites. Among individuals with HTN and DM comorbidity, aspirin use notably associated with lower risk of overall CRC (OR, 0.39; 95% CI, 0.21-0.72), proximal colon (OR, 0.32; 95% CI, 0.13-0.71) and rectal cancer (OR, 0.27; 95% CI, 0.08-0.97), but not distal colon cancer (OR, 0.58; 95% CI, 0.27-1.24). CONCLUSION: This study showed that aspirin use is negatively associated with overall and site-specific CRC, even among individuals with HTN and DM comorbidity.

The interaction between magnesium intake, the genetic variant INSR rs1799817 and colorectal cancer risk in a Korean population: a case-control study.

Magnesium may have a significant impact on the development of cancer. However, the relationship between magnesium intake and the risk of colorectal cancer (CRC) is unclear. Therefore, we evaluated the association between magnesium intake and the risk of CRC, and we investigated how the insulin receptor (INSR) rs1799817 variant impacts this relationship. Data from 1,420 CRC patients and 2,840 controls from the Korean National Cancer Centre were analysed. A higher intake of magnesium was associated with a reduced risk of CRC in the total population (odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.52-0.81). We found that G + carriers of INSR rs1799817 with higher magnesium intake had a significantly lower risk of CRC (p for interaction = 0.003). Our findings indicated that high magnesium intake could be associated with a decreased risk of CRC, and this association could be modified by the INSR rs1799817 variant.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial.

BACKGROUND: For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. METHODS: This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. DISCUSSION: The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. TRIAL REGISTRATION: Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

FDG metabolic parameter-based models for predicting recurrence after upfront surgery in synchronous colorectal cancer liver metastasis.

OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.

Effects of prior endoscopic resection on recurrence in patients with T1 colorectal cancer who underwent radical surgery.

PURPOSE: Endoscopic resection (ER) is a reliable treatment for early colorectal cancer without lymph node metastasis. We aimed to examine the effects of ER performed prior to T1 colorectal cancer (T1 CRC) surgery by comparing long-term survival after radical surgery with prior ER to that after radical surgery alone. METHODS: This retrospective study included patients who underwent surgical resection of T1 CRC at the National Cancer Center, Korea, between 2003 and 2017. All eligible patients (n = 543) were divided into primary and secondary surgery groups. To ensure similar characteristics between the groups, 1:1 propensity score matching was used. Baseline characteristics, gross and histological features, along with postoperative recurrence-free survival (RFS) between the two groups were compared. Cox proportional hazard model was used to identify the risk factors affecting recurrence after surgery. Cost analysis was performed to examine the cost-effectiveness of ER and radical surgeries. RESULTS: No significant differences were observed in 5-year RFS between the two groups in matched data (96.9% vs. 95.5%, p = 0.596) and in the unadjusted model (97.2% vs. 96.8%, p = 0.930). This difference was also similar in subgroup analyses based on node status and high-risk histologic features. ER before surgery did not increase the medical costs of radical surgery. CONCLUSION: ER prior to radical surgery did not affect the long-term oncologic outcomes of T1 CRC or significantly increased the medical costs. Attempting ER first for suspected T1 CRC would be a good strategy to avoid unnecessary surgery without concerns of worsening cancer-related prognosis.

Safety of early surgery after self-expandable metallic stenting for obstructive left-sided colorectal cancer.

BACKGROUND: Self-expanding metallic stenting (SEMS) is usual for the temporary resolution of obstructive left-sided colorectal cancer (CRC) as a bridge to elective surgery. However, there is no consensus regarding adequate time intervals from stenting to radical surgery. The aim of this study was to identify the optimal time interval that results in favorable short- and long-term outcomes. METHODS: Data on patients with obstructive left-sided CRC who underwent elective radical surgery after clinically successful SEMS deployment in five tertiary referral hospitals from 2004 to 2016 were analyzed, retrospectively. An inverse probability treatment-weighted propensity score analysis was used to minimize bias. Postoperative short- and long-term outcomes were compared between two groups: an early surgery (within 8 days) group and delayed surgery (after 8 days) group. RESULTS: Of 311 patients, 148 (47.6%) underwent early and 163 (52.4%) underwent delayed surgery. The median surgery interval was 9.0 days. After adjustment, the groups had similar patient and tumor characteristics. In terms of short-term outcomes, there was no difference in hospitalization length or postoperative complications. No deaths were observed. With a median follow-up of 71.0 months, no significant difference was observed between the groups in 5-year overall survival (early vs. delayed surgery: 79.6% vs. 71.3%, P = 0.370) and 5-year disease-free survival (early vs. delayed surgery: 59.1% vs. 60.4%, P = 0.970). CONCLUSIONS: In obstructive left-sided CRC, the time interval between SEMS and radical surgery did not significantly influence short- and long-term outcomes. Therefore, early surgery after SEMS could be suggested if there is no reason to postpone surgery for preoperative medical optimization.

Vitamin E intake and paraoxonase 1 (PON1) rs662 genetic polymorphism are associated with colorectal cancer risk in a Korean population.

Vitamin E and paraoxonase 1 (PON1) are associated with cancer development. However, their interactive effect on colorectal cancer (CRC) risk is inconclusive. We conducted a case-control study including 1,351 CRC patients and 2,670 controls at the Korean National Cancer Centre (KNCC). There was an inverse association between vitamin E intake and CRC risk (odds ratio (OR) = 0.31; 95% confidence interval (CI) = 0.22-0.42). We identified a reduced CRC risk among individuals with CC genotype of PON1 rs662 polymorphism compared with subjects carrying the T allele (OR = 0.74; 95% CI = 0.61-0.90). The highest interaction between vitamin E intake and PON1 rs662 variants was significant for the subjects carrying the CC genotype (p-interaction = 0.014). This study provided further supporting evidence that vitamin E intake is associated with lower odds of CRC. Furthermore, the activity of vitamin E is strengthened among individuals carrying C allele of the PON1 rs662 polymorphism.

Coffee consumption and its interaction with the genetic variant AhR rs2066853 in colorectal cancer risk: a case-control study in Korea.

The bioactive compounds in coffee have several antioxidant properties that may beneficially impact colorectal cancer (CRC) development. The aryl hydrocarbon receptor (AhR) is an important transcription factor that regulates an enzyme related to the caffeine metabolism pathway. We investigated the modification effect on coffee of AhR gene polymorphism in the risk of CRC. A case-control study was conducted with 699 cases and 1393 controls to investigate the interaction between coffee intake and the AhR rs2066853 variant in CRC risk. The odds ratios (ORs) and 95% confidence intervals (CIs) were assessed using multiple logistic regression analyses. We observed a significant protective effect of coffee against CRC in the overall and male populations. Consuming three or more cups of coffee per day may significantly lower CRC risk in all subjects by 77% and in men by 83% (OR = 0.23, 95% CI: 0.14-0.39 and OR = 0.17, 95% CI: 0.09-0.34, respectively, P-trends < 0.001). No association between AhR rs2066853 and CRC risk was found. In the dominant model, the G/G genotype had a strongest synergistic effect with coffee on protection against CRC (OR = 0.12, 95% CI: 0.06-0.26, P-interaction = 0.014). The interaction remained significant in men and the distal colon cancer subgroup. In the additive model, the interaction was clearly shown strongest in G/G carriers (OR = 0.12, 95% CI: 0.06-0.27, P-interaction = 0.039), followed by A/A and G/A carriers. The interaction remained significant in men and the rectal cancer subgroup. In conclusion, the protective effect of coffee on CRC risk might interact with the genetic variant AhR rs2066853, and this joint effect was determined by sex and site-specific cancer.

Developing and validating polygenic risk scores for colorectal cancer risk prediction in East Asians.

Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We used genome-wide association study (GWAS) data from 22 702 cases and 212 486 controls of Asian ancestry to develop PRSs and validated them in two case-control studies (1454 Korean and 1736 Chinese). Eleven PRSs were derived using three approaches: GWAS-identified CRC risk SNPs, CRC risk variants identified through fine-mapping of known risk loci and genome-wide risk prediction algorithms. Logistic regression was used to estimate odds ratios (ORs) and area under the curve (AUC). PRS115-EAS , a PRS with 115 GWAS-reported risk variants derived from East-Asian data, validated significantly better than PRS115-EUR derived from European descendants. In the Korea validation set, OR per SD increase of PRS115-EAS was 1.63 (95% CI = 1.46-1.82; AUC = 0.63), compared with OR of 1.44 (95% CI = 1.29-1.60, AUC = 0.60) for PRS115-EUR . PRS115-EAS/EUR derived using meta-analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115-EAS/EUR have a 2.52-fold elevated CRC risk compared with the medium (41-60th) risk group and have a 12% to 20% risk of developing CRC by age 85. PRSs constructed using results from fine-mapping and genome-wide algorithms did not perform as well as PRS115-EAS and PRS115-EAS/EUR in risk prediction, possibly due to a small sample size. Our results indicate that CRC PRSs are promising in predicting CRC risk in East Asians and highlights the importance of using population-specific data to build CRC risk prediction models.

Development and validation of a novel strong prognostic index for colon cancer through a robust combination of laboratory features for systemic inflammation: a prognostic immune nutritional index.

BACKGROUND: Systemic inflammation is associated with survival outcomes in colon cancer. However, it is not well-known which systemic inflammatory marker is a powerful prognostic marker in patients with colon cancer. METHODS: A total of 4535 colon cancer patients were included in this study. We developed a novel prognostic index using a robust combination of seven systemic inflammation-associated blood features of the discovery set. The predictability and generality of the novel prognostic index were evaluated in the discovery, validation and replication sets. RESULTS: Among all combinations, the combination of albumin and monocyte count was the best candidate expression. The final formula of the proposed novel index is named the Prognostic Immune and Nutritional Index (PINI). The concordance index of PINI for overall and progression-free survival was the highest in the discovery, validation and replication sets compared to existing prognostic inflammatory markers. PINI was found to be a significant independent prognostic factor for both overall and progression-free survival. CONCLUSIONS: PINI is a novel prognostic index that has improved discriminatory power in colon cancer patients and appears to be superior to existing prognostic inflammatory markers. PINI can be utilised for decision-making regarding personalised treatment as the complement of the TNM staging system.

Subpopulation analysis of survival in high-risk T1 colorectal cancer: surgery versus endoscopic resection only.

BACKGROUND AND AIMS: This study aimed to assess the long-term survival of patients with T1 colorectal cancer (CRC) after local or surgical resection considering the type and number of risk factors for lymph node metastasis. METHODS: This study included patients with high-risk T1 CRC who underwent therapeutic resection at the National Cancer Center, Korea between January 2001 and December 2014. Risk factors included positive resection margin, high-grade histology, deep submucosal invasion, vascular invasion, budding, and no background adenoma (BGA). We statistically divided the population into favorable or unfavorable subpopulations. The favorable subpopulation included the following 5 combinations of risk factors: positive margin only or unconditional for margin status, deep submucosal invasion only, budding only, no BGA only, and budding + no BGA. We analyzed the survival rate according to the resection type (local or surgical) in the total cohort and in each subpopulation. RESULTS: Eighty-one and 466 patients underwent local and surgical resections, respectively. The distant recurrence-free survival (DRFS) and overall survival (OS) rates were significantly high in the surgical group (hazard ratio [HR], .20; 95% confidence interval [CI], .06-.61; P = .0045 and HR, .41; 95% CI, .25-.70; P = .0010, respectively). In the favorable subpopulation, both DRFS and OS rates were not significantly different between the surgical and local groups (HR, .26; 95% CI, .02-4.19; P = .3431 and HR, .58; 95% CI, .27-1.23; P = .1534, respectively). CONCLUSIONS: Intensive surveillance without additional surgery may be another option in selected cases after of high-risk T1 CRC endoscopic resection.

Interactive effect of the empirical lifestyle index for insulin resistance with the common genetic susceptibility locus rs2423279 for colorectal cancer.

The aim of this study is to examine the empirical insulinemic potential consisting of dietary and lifestyle factors and the interactive effect with the common genetic susceptibility locus rs2423279 on the risk of colorectal cancer (CRC). This case-control study was conducted with 923 CRC patients and 1846 controls. The empirical measures for assessing the insulinemic potential, namely, the empirical dietary index for hyperinsulinemia (EDIH), for insulin resistance (EDIR), the empirical lifestyle index for hyperinsulinemia (ELIH), and for insulin resistance (ELIR), were calculated based on semiquantitative food frequency questionnaire and lifestyle questionnaire. A genetic variant of rs2423279 was genotyped. The CRC patients were more likely to score in the highest quartile for the ELIH (OR 2·90, Q4 v. Q1, 95 % CI (2·01, 4·19), Pfor trend < 0·001), EDIR (OR 3·32, Q4 v. Q1, 95 % CI (2·32, 4·74), P < 0·001) and ELIR (OR 2·79, Q4 v. Q1, 95 % CI (1·96, 3·97), P < 0·001) than the controls. The significant effect between the ELIR, which assesses dietary and lifestyle patterns related to insulin resistance, and C allele carriers of rs2423279 was stronger than that for homozygous T allele carriers (OR 2·50, 95 % CI (1·78, 3·51), Pfor interaction = 0·034). The empirical insulinemic potential for insulin resistance might have interactive effects with the rs2423279 polymorphism on the risk of CRC. The results of this study suggest the basis of the metabolic impact of the insulin response on colorectal carcinogenesis.

Comparison of tumor regression grade and clinical stage based on MRI image as a selection criterion for non-radical management after concurrent chemoradiotherapy in locally advanced rectal cancer: a multicenter, retrospective, cross-sectional study.

PURPOSE: There has been no comparative study on the clinical value of magnetic resonance tumor regression grade (mrTRG)1-2 and ycT0-1N0 for the prediction of ypT0-1N0 after concurrent chemoradiotherapy (CCRT) for rectal cancer. We compared the diagnostic performance between mrTRG1-2 and ycT0-1N0 for predicting ypT0-1N0 as a selection criterion for non-radical management after CCRT in locally advanced rectal cancer. METHODS: This retrospective study enrolled 291 patients from three referral hospitals between January 2018 and March 2020. The diagnostic performance of ycT0-1N0 and mrTRG1-2 for the prediction of ypT0-1N0 was compared in terms of sensitivity, specificity, positive-predictive value, negative-predictive value, and area under the curve (AUC). RESULTS: Sixty-eight patients (23.4%) achieved ypT0-1N0. Nineteen patients (6.5%) had ycT0-1N0, and 91 patients (31.2%) had mrTRG1-2. For predicting ypT0-1N0, ycT0-1N0 had a sensitivity of 16.2% (95% confidence interval [CI]: 8.36‒27.10) and positive-predictive value of 57.9% (95% CI: 36.57‒76.63), while mrTRG1-2 had a sensitivity of 58.8% (95% CI: 46.23‒70.63) and positive-predictive value of 44.0% (95% CI: 36.46‒51.74). When predicting ypT0-1N0, mrTRG1-2 showed a higher AUC (0.680, 95% CI: 0.604‒0.756) than ycT0-1N0 (0.563, 95% CI: 0.481‒0.645) (P < 0.001). CONCLUSION: mrTRG1-2 might be a better indicator than ycT0-1N0 for the selection of non-radical management of advanced rectal cancer post-CCRT. However, additional diagnostic tools are required for predicting ypT0-1N0 because mrTRG1-2 or yc stage on MRI has insufficient evidence for diagnosing ypT0-1N0.

Dietary methyl donor nutrients, DNA mismatch repair polymorphisms, and risk of colorectal cancer based on microsatellite instability status.

PURPOSE: Colorectal cancer (CRC) is a heterogeneous disease caused by complex interplay among the diet, the environment, and genetics involving numerous molecules and pathological pathways. This study aimed to determine whether methyl donor nutrients are associated with CRC and how these associations are altered by DNA mismatch repair (MMR) genes. METHODS: In total, 626 cases and 838 age- and sex-matched controls were recruited for this case-control study. A validated food frequency questionnaire was used to assess seven methyl donor nutrients (vitamin B2, niacin, B6, folate, B12, methionine, and choline). MMR polymorphisms were genotyped using an Illumina MEGA-Expanded Array. For the 626 patients, the microsatellite instability status and immunohistochemical expression of MMR proteins were analyzed. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the methyl donor nutrients, B2, niacin, B6, folate, and methionine were inversely associated with CRC risk, while a high intake of choline increased CRC. Regarding MMR genes, three hMSH3 polymorphisms (rs32952 A > C, rs41097 A > G, and rs245404 C > G) reduced CRC risk. Regarding gene-diet interactions, a stronger interaction effect was observed in G allele carriers of hMSH3 rs41097 with high niacin intake than in AA carriers with low niacin intake (OR, 95% CI = 0.49, 0.33-0.72, P for interaction = 0.02) in subgroups of patients with distal colon cancer (P for interaction = 0.008) and MMR proficiency with microsatellite stability (P for interaction = 0.021). CONCLUSIONS: Methyl donor nutrients may affect CRC risk leading to a balance in the MMR machinery.

The interaction between glycemic index, glycemic load, and the genetic variant ADIPOQ T45G (rs2241766) in the risk of colorectal cancer: a case-control study in a Korean population.

PURPOSE: The glycemic index (GI), glycemic load (GL), and adiponectin level contribute to glycemic response and insulin sensitivity in the body. Studies have shown that tumor development is related to glycemic disorders; however, the results are contradictory. We aimed to investigate the association of GI and GL with colorectal cancer (CRC) risk in a Korean population and their possible interactions with the genetic variant ADIPOQ T45G. METHODS AND RESULTS: A case-control study including 2096 participants with 695 CRC cases was conducted. The results showed that diets with high GI or GL were significantly associated with an increased risk of CRC [odds ratio (OR) = 5.44, 95% confidence interval (CI) 3.85-7.68; OR = 4.43, 95% CI 3.18-6.15, respectively; all p-trends < 0.001]. Moreover, even with a low-GI and low-GL diet, G/G genotype carriers may have 2.93-fold and 3.77-fold higher risk of rectal cancer compared to carriers of other genotypes (T/T + T/G), (OR = 2.93, 95% CI 1.01-8.59, p-interaction = 0.011 for GI; OR = 3.77, 95% CI 1.46-9.77, p-interaction = 0.025 for GL). CONCLUSIONS: Overall, our study suggests positive associations of GI and GL with CRC risk. Moreover, the associations of GI and GL with rectal cancer risk could be modified by ADIPOQ T45G in a Korean population. Further studies with larger sample sizes are needed to confirm our findings.