分子疫学研究における統計的方法論の展開：がんサブタイプへの取り組み

要旨あり疫学研究のデザインとデータ解析：最近の理論的展開と実践総合報

Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review

Background: KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear. Methods: We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI. Results: KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation]. Conclusions: Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted

TGFBR2 and BAX Mononucleotide Tract Mutations, Microsatellite Instability, and Prognosis in 1072 Colorectal Cancers

Mononucleotide tracts in the coding regions of the TGFBR2 and BAX genes are commonly mutated in microsatellite instability-high (MSI-high) colon cancers. The receptor TGFBR2 plays an important role in the TGFB1 (transforming growth factor-β, TGF-β) signaling pathway, and BAX plays a key role in apoptosis. However, a role of TGFBR2 or BAX mononucleotide mutation in colorectal cancer as a prognostic biomarker remains uncertain.We utilized a database of 1072 rectal and colon cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusted for clinical, pathological and molecular features including the CpG island methylator phenotype (CIMP), LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. MSI-high was observed in 15% (162/1072) of all colorectal cancers. TGFBR2 and BAX mononucleotide mutations were detected in 74% (117/159) and 30% (48/158) of MSI-high tumors, respectively. In Kaplan-Meier analysis as well as univariate and multivariate Cox regression analyses, compared to microsatellite stable (MSS)/MSI-low cases, MSI-high cases were associated with superior colorectal cancer-specific survival [adjusted HR, 0.34; 95% confidence interval (CI), 0.20-0.57] regardless of TGFBR2 or BAX mutation status. Among MSI-high tumors, TGFBR2 mononucleotide mutation was associated with CIMP-high independent of other variables [multivariate odds ratio, 3.57; 95% CI, 1.66-7.66; p = 0.0011].TGFBR2 or BAX mononucleotide mutations are not associated with the patient survival outcome in MSI-high colorectal cancer. Our data do not support those mutations as prognostic biomarkers (beyond MSI) in colorectal carcinoma

Interactive assistance via eHealth for small- and medium-sized enterprises’ employer and health care manager teams on tobacco control (eSMART-TC): protocol for a cluster randomized hybrid type II trial (N-EQUITY2101/J-SUPPORT2102)

Abstract Background Tobacco control should be a higher public health priority in Japan. Some workplaces provide smoking cessation support and connect employees to effective smoking cessation treatments such as outpatient clinics. However, tobacco control measures have not been sufficiently implemented in Japan, especially in small- and medium-sized enterprises (SMEs), where resources are limited. Organizational commitment and consistent leadership are crucial to facilitate implementation, but research on whether supporting organizational leaders leads to health behavior changes among employees is limited. Methods This hybrid type II cluster randomized effectiveness implementation trial (eSMART-TC) aims to examine the effects of interactive assistance for SME management on health and implementation outcomes. We will provide interactive assistance to employers and health managers for 6 months, aiming to promote the utilization of reimbursed smoking cessation treatments by public health insurance and to implement smoke-free workplaces. The intervention will consist of three strategies: supporting employees through campaigns, tailored ongoing facilitation, and ensuring executive engagement and support. The primary health and implementation outcomes will be salivary cotinine-validated 7-day point-prevalence abstinence rate, and the adoption of two recommended measures (promoting utilization of smoking cessation treatment and implementing smoke-free workplaces) 6 months after the initial session, respectively. Other outcomes for implementation (e.g., penetration of smoking cessation clinic visits), health (e.g., salivary cotinine-validated 7-day point-prevalence abstinence rate at 12 months), and process (e.g., adherence and potential moderating factors) will be collected via questionnaires, interviews, logbooks, and interventionists’ notes at 6 and 12 months. An economic analysis will be undertaken to assess the cost-effectiveness of the implementation interventions at 12 months. Discussion This will be the first cluster randomized controlled trial to evaluate the effectiveness of an implementation intervention with interactive assistance for employers and health managers in SMEs on smoking cessation and implementation of evidence-based tobacco control measures in SMEs. The findings of this trial targeting management in SMEs have the potential to accelerate the implementation of evidence-based smoking cessation methods as well as abstinence rates among employees in SMEs across Japan. Trial registration The study protocol has been registered in the UMIN Clinical Trials Registry (UMIN-CTR; ID: UMIN000044526). Registered on 06/14/2021