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Genes selected for the study using GO and GeneCard databases and literature search to represent 10 epigenetic sub-pathways, specifically DNA methylation, DNA demethylation, histone acetylation, histone deacetylation, chromatin remodeling, histone methylation, histone demethylation, other histone modification, chromatin modification and histones.

Locuszoom plots of the regions with pleiotropic association. (A) TNP1 (2q35), (B) RUVBL1 and GATA2 (3q21), (C) PHC3 (3q26), (D) TET2 (4q24), (E) POU5F1, BAG6 and EHMT2 (6p21),(F) L3MBTL3 (6q23), (G) HDAC9 (7p21), (H) LOXL2 (8p21), (I) BRCA2 (13q12), (J) WDR61 and MORF4L1 (15q25), (K) TADA2A (17q12), (L) BABAM1 (19p13), (M) DPF1 (19q13) and (N) TGFB1 (19q13).

Supplementary table and figure legends

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50–79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5′-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (−13.0%; 95% CI: −17.3%, −8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene–biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

Objective:This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds.Summary Background Data:ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established.Methods:Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test.Results:Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [ORSEER-18= 1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR= 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18= 0.98, 95% CI = 0.98-0.99; HRNCR= 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration.Conclusions:In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.

Fecal immunochemical tests (FITs) are used for colorectal cancer (CRC) screening in a large and increasing number of countries (1). Multiple large-scale screening cohorts have demonstrated that FITs detect the majority of CRCs. In a meta-analysis from 2019, pooled sensitivity ranged from 71% (95% confidence interval [CI]: 56%–83%) to 91% (84%–95%), and specificity ranged from 90% to 95% (2). However, little is known on the sensitivity of FIT for detecting CRC at individual stages because many of the individual studies did not report stage-specific sensitivities, and no meta-analysis of stage-specific sensitivities was conducted. The ability of FITs to detect CRC at early stages is of particular relevance for their use in CRC screening, as chances of cure of CRC are dramatically higher when they are detected in earlier rather than later stages (3). Despite numerous studies reporting on stage-specific test characteristics of FIT (4–43), only one study to date (22) focused on this outcome. Given the small case numbers from the studies conducted among asymptomatic screening participants, obtaining reasonably precise stage-specific estimates of sensitivity from such studies is difficult if not impossible. Much larger case numbers have been included in the studies conducted among symptomatic participants who were diagnosed with CRC following colonoscopy for clarification of symptoms (symptomatic/diagnostic cohorts) or who were recruited after CRC diagnosis and compared with healthy controls in a clinical setting (case-control studies). Although overall sensitivity is expected to be higher among these patient groups than among average-risk participants undergoing screening colonoscopy due to spectrum bias, stage-specific sensitivity may be comparable (44). In that case, the possibility of recruiting larger number of CRC patients in such settings might enable estimating stage-specific sensitivities of FIT irrespective of the study type at much higher levels of precision. Our aim was therefore to systematically review and compare the estimates of the stage-specific sensitivity of FIT for CRC detection from various types of studies and, if possible, summarize them to derive reasonably precise estimates of stage-specific sensitivities.

Objectives Many risk scores have been proposed to predict presence of advanced colorectal neoplasms, but a comprehensive comparison conducted in the same population is sparse. The aim of this study was to evaluate and directly compare the diagnostic performance of published risk prediction models for advanced colorectal neoplasms. Methods Data were drawn from 2 cohorts of subjects undergoing screening colonoscopy in Germany, i.e., KolosSal (n = 16,195) and BliTz (n = 7,444). Absolute risks and relative risks were generated for the presence of at least 1 advanced neoplasm, taking the lowest risk group as the reference group. Performance of risk models was assessed by the area under the receiver operating characteristic curve (AUC) and compared by the net reclassification improvement. Results The 2 cohorts included 1,917 (11.8%) and 848 (11.4%) participants with advanced neoplasm, respectively. Absolute risks were mostly between 5% and 10% among participants in the lowest risk group and between 15% and 20% among participants in the highest risk group, and relative risks mostly ranged from 2.0 to 4.0 across the risk models in both cohorts. The AUCs ranged from 0.58 to 0.65 in KolosSal and from 0.57 to 0.61 in BliTz for all risk scores. Compared to models with lower AUC, classification was significantly improved in most models with higher AUC. Discussion Risk models for advanced colorectal neoplasms generally yielded modest discriminatory power, despite some variation in performance between models. Future studies should evaluate the performance of these risk models in racially diverse populations and investigate possible extensions, such as combination with polygenic risk scores.

Early detection of colorectal neoplasms can reduce the disease burden of colorectal cancer by timely intervention of individuals at high risk. Our aim was to evaluate a joint environmental-genetic risk score as a risk stratification tool for early detection of advanced colorectal neoplasm (ACRN). Known environmental risk factors and high-risk genetic loci were summarized into risk scores for ACRN in 1014 eligible participants of a screening study. The performances of single and joint environmental-genetic scores were evaluated with estimates and 95% confidence intervals (CI) of the absolute risk, relative risk and predictive ability using the area under the curve (AUC). Individuals with higher environmental risk scores showed increasing ACRN risk, with 3.1-fold for intermediate risk and 4.8-fold for very high risk, compared to the very low environmental risk group. Similarly, individuals with higher genetic risk scores showed increasing ACRN risk, with 2.2-fold for intermediate risk and 3.5-fold for very high risk, compared to the lowest genetic risk group. Moreover, the joint environmental–genetic score improved the ACRN risk stratification and showed higher predictive values (AUC = 0.64; 95%CI = 0.60–0.67) with substantial difference (p = 0.0002) compared to the single environmental score (0.58; 0.55–0.62). The integration of environmental and genetic factors looks promising for improving targeting individuals at high-risk of colorectal neoplasm. Applications in practical screening programs require optimization with additional genetic and other biomarkers involved in colorectal carcinogenesis. (Less)

Background Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I–II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. Methods Data of stage I–II PaC patients resected and receiving chemotherapy in 2003–2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. Results A total of 11,837 resected PaC patients were analyzed, with median survival time of 18–23 months and 3-year survival rates of 21–31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. Conclusions In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly. Electronic supplementary material The online version of this article (10.1186/s12916-019-1304-y) contains supplementary material, which is available to authorized users.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency. Radium Hospital Foundation (Oslo, Norway)

Objectives Most studies identifying inflammatory markers for early detection of colorectal cancer (CRC) were conducted using clinically manifest cases. We aimed to identify circulating inflammatory biomarkers for early detection of CRC and validate them in both a clinical setting and a true screening setting. Study Design and Setting A total of 92 inflammatory proteins were quantified in baseline plasma samples from individuals clinically diagnosed with CRC and neoplasm-free controls matched on age and sex (training set). A multimarker panel was selected and evaluated in samples from another clinical setting (validation set C) and a screening setting (validation set S). Results In the training set (N = 330), a five-biomarker signature was selected that provided an area under curve (AUC) of 0.85 and 60.9% sensitivity to detect CRC at 90% specificity. When this algorithm was applied to validation set C (N = 318), the AUC (0.80) and sensitivity (49.5%) at 90% specificity for CRC diagnosis were only slightly lower than those in the training set. By contrast, the diagnostic performance of the algorithm in validation set S (N = 126) from a true screening setting was much poorer, with an AUC of 0.59 and a sensitivity of 28.6% at 90% specificity. Conclusions An inflammation-related protein panel with apparently good diagnostic properties for CRC detection was identified and confirmed in an independent clinical validation set. However, the biomarker combination performed substantially worse in a validation sample from a true screening setting. Our results underline the importance of validation in screening settings subsequently to novel signature discovery for cancer early detection.

INTRODUCTION Fecal immunochemical tests (FITs) for hemoglobin are increasingly used in colorectal cancer (CRC) screening. The use of uniform positivity thresholds (cutoffs) within screening populations is expected to imply lower positive predictive values (PPVs) and higher numbers of colonoscopies needed (numbers needed to scope [NNSs]) to detect advanced neoplasms among screening participants at lower risk compared with those at higher risk. We aimed to assess such variation and its potential implications in a large screening cohort. METHODS A quantitative FIT (FOB Gold; Sentinel Diagnostics, Milan, Italy) was conducted in fecal samples collected by 4,332 participants of screening colonoscopy before bowel preparation. Participants were classified into 3 risk groups (low, medium, and high) by tertiles of a previously derived risk-factor-based risk score. We determined the variation of PPVs and NNSs for detecting advanced neoplasms (i.e., CRC or advanced adenoma) when using the same FIT cutoffs and variation of FIT cutoffs that would yield uniform PPVs across risk groups. RESULTS When a fixed FIT cutoff of 10 μg/g was used, the PPV increased from 23.3% to 41.8% from the low- to the high-risk group, with NNS decreasing from 4.3 to 2.4 (P < 0.001). Similar variations of PPVs and NNSs across risk groups were observed at higher FIT cutoffs. When risk group-specific cutoffs were defined to achieve fixed PPVs of 25%, 30%, and 35% across all risk groups, cutoffs varied from 5.3 to 11.4, 6.5 to 18.7, and 7.5 to 31.0 μg hemoglobin/g feces, respectively, between high- and low-risk groups (P < 0.05 for all differences). DISCUSSION Using risk-adapted cutoffs may help to achieve target levels of PPV and NNS and might be an option to consider for personalized FIT-based CRC screening.

An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.

Background: Resection is the cornerstone of curative treatment for many nonmetastatic gastric cancers (GCs), but the population treatment patterns remains largely unknown. This large international population-based study aimed at investigating the treatment patterns and trends for nonmetastatic GC in Europe and the United States and at exploring factors associated with resection. Methods: Data of patients with microscopically confirmed primary invasive GC without distant metastasis from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, Slovenia, and Estonia and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program were retrieved. Age-standardized treatment rates were computed and trends were evaluated using linear regression. Associations of resection with patient and tumor characteristics were analyzed using multivariable-adjusted log-binomial regression. Analysis was performed in each country respectively without pooling. Results: Together 65 707 nonmetastatic GC patients diagnosed in 2003-2016 were analyzed. Age-standardized resection rates significantly decreased over years in all countries (by 4-24%). In 2013-2014, rates varied greatly from 54 to 75%. Patients with increasing ages, cardia cancers, or cancers invading adjacent structure were significantly less frequently resected. Resection was further associated with sex, performance status, comorbidities, tumor histology, tumor size, hospital type, and hospital volume. Association patterns and strengths varied across countries. After multivariable adjustment, resection rates remained decreasing (prevalence ratio = 0.97-0.995 per year), with decreasing trends consistently seen in various subgroups. Conclusions: Nonmetastatic GCs were less frequently resected in Europe and the United States in the early 21st century. Resection rates varied greatly across countries and appeared not to be optimal. Various factors associated with resection were revealed. Our findings can help to identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based GC management strategies. ∙ In Europe and the United States, nonmetastatic gastric cancers were less frequently resected in the early 21st century. ∙ Resection rates varied greatly across countries and appeared not optimal. ∙ Various factors associated with resection were revealed. ∙ Our findings identify differences and possibly modifiable places in clinical practice and provide important novel references for designing effective population-based management strategies.

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003-2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003-2005 to 2012-2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012-2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HR het = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HR het = 0.82, 95% CI: 0.68–0.99 and rs2847149: HR het = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HR het = 1.28, 95% CI: 1.07–1.53; HR hzv = 2.02, 95% CI:1.46–2.80; HR logAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P

DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92

The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low-/high-risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013) and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9-24%) of Stage II and over half (range 55-68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67-0.99), Belgium (0.73; 0.59-0.90) and Sweden (0.58; 0.44-0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43-0.50), Belgium (0.46; 0.41-0.50) and Sweden (0.48; 0.43-0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high-risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.

Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate–corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)–negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10–1.19; q = 6.87 × 10−5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91–0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03–1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816–25. ©2017 AACR.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.

Epigenome-wide association studies have established methylation patterns related to smoking, the major risk factor of lung cancer (LC), which are distinct from methylation profiles disclosed in LC patients. This study simultaneously investigated associations of smoking-associated and LC-related methylation markers with LC mortality. DNA methylation was determined by HM450K assay in baseline blood samples of 1,565 older adults in a population-based case-cohort study. The associations of 151 smoking-associated CpGs (smoCpGs) and 3,806 LC-related CpGs (caCpGs) with LC mortality were assessed by weighted Cox regression models, controlling for potential confounders. Multi-loci methylation scores were separately constructed based on smoCpGs and caCpGs. During a median follow-up of 13.8 years, 60 participants who had a first diagnosis of LC died from LC. The average time between sample collection and LC diagnosis was 5.8 years. Hypomethylation at 77 smoCpGs and 121 caCpGs, and hypermethylation at 4 smoCpGs and 66 caCpGs were associated with LC mortality. The associations were much stronger for smoCpGs than for caCpGs. Hazard ratios (95% CI) were 7.82 (2.91-21.00) and 2.27 (0.75-6.85), respectively, for participants in highest quartile of Score I (based on 81 smoCpGs) and Score II (based on 187 caCpGs), compared with participants in the corresponding lower three quartiles. Score I outperformed Score II, with an optimism-corrected C-index of 0.87 vs. 0.77. In conclusion, although methylation changes of both smoking-associated and LC-related genes are associated with LC mortality, only smoking-associated methylation markers predict LC mortality with high accuracy, and may thus serve as promising candidates to identify high risk populations for LC screening.

Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.

Background Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis. Methods Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression. Results Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable-adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50–4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (Ptrend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45–6.58, Ptrend = 0.005), 2.24 (95% CI, 1.18–4.44, Ptrend = 0.021) and 3.92 (95% CI, 1.51–12.18, Ptrend = 0.003), respectively. Conclusions Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening.

Background The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. Methods Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003–2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003–2005, 2006–2008, and 2009–2011) were further examined using the log-rank test. Results In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20–34% (

Table S1. Selection of contacted national population-based cancer registries in Europe. Table S2. General information on participating population-based registries. Table S3. Inclusion codes according to International Classification of Diseases for Oncology, Third Edition. Table S4. Unadjusted survival proportions in patients with overall and resected stages III–IV PaC. Figure S1. Kaplan-Meier curves (solid lines) of age group-specific survival in overall (upper panel) and resected patients (lower panel) with TNM stages III–IV pancreatic cancers. The dashed lines indicate the 95% confidence limits, and the shadows represent the Hall-Wellner confidence bands. Numbers of patients at risk are also reported. Median survival is in months. IQR interquartile range. Figure S2. Kaplan-Meier curves (solid lines) of age group-specific survival in microscopically confirmed overall TNM stages I–II (upper panel) and stages III–IV pancreatic cancer patients (lower panel). The dashed lines indicate the 95% confidence limits, and the shadows represent the Hall-Wellner confidence bands. Numbers of patients at risk are also reported. Median survival is in months. IQR interquartile range. Figure S3. Changes in 1-month survival over calendar periods among overall and resected patients with stages I–II and III–IV pancreatic cancers. Figure S4. Changes in 3-month survival over calendar periods among overall and resected patients with stages I–II and III–IV pancreatic cancers. Figure S5. Changes in 12-month survival over calendar periods among overall and resected patients with stages I–II and III–IV pancreatic cancers. Figure S6. Changes in 36-month survival over calendar periods among overall and resected patients with stages I–II and III–IV pancreatic cancers. Figure S7. Changes in 60-month survival over calendar periods among overall and resected patients with stages I–II and III–IV pancreatic cancers. Supplementary Results. Patient characteristics. (DOCX 3259 kb)

The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This international large-scale population-based study aimed to investigate the real-world application of chemotherapy and radiotherapy for resected and unresected PaC in Europe and USA. Population-based data from multiple European national cancer registries and the US Surveillance, Epidemiology and End Results (SEER)-18 database during 2003–2014 were analyzed. Temporal trends and geographical variations in the application rates of chemotherapy and radiotherapy were quantified using age standardization. Associations of treatment with demographic and clinical characteristics were assessed using multivariable logistic regression. A total of 141,533 PaC patients were analyzed. From 2003–2005 to 2012–2014, chemotherapy administration rates increased in most countries and more strongly among resected patients, while radiation rates were generally low with a slight decline or no obvious trend. In 2012–2014, 12.5% (Estonia) to 61.7% (Belgium) of resected and 17.1% (Slovenia) to 56.9% (Belgium) of unresected patients received chemotherapy. Radiation was administered in 2.6% (Netherlands) to 32.6% (USA) of resected and 1.0% (USA) to 6.0% (Belgium) of unresected patients. Strong temporal and geographical variations were observed. Patterns and strengths of associations of treatment administration with various demographic and clinical factors differed substantially between resected and unresected cancers and varied greatly across countries. Conclusively, administration of chemotherapy but not radiotherapy for PaC increased during the last decade in Europe and USA. Treatment rates were low and the uptake strongly varied across countries, highlighting the need for standardization in PaC treatment to improve patient care.

Background Neoadjuvant therapy improves survival of patients with clinical stage II and III rectal cancer in clinical trials. In this study, we investigated the administration of neoadjuvant radiotherapy (neo-RT) and neoadjuvant chemoradiotherapy (neo-CRT) and its association with survival in resected patients in 2 European countries (The Netherlands and Sweden) and at 3 specialist centers. Materials and Methods Administration of neoadjuvant treatment (all registries) and overall survival after surgery in The Netherlands and Sweden were assessed. Hazard ratios (HRs) were obtained using Cox regression adjusted for potential confounders. Results A total of 16,095 rectal cancer patients with clinical stage II and III were eligible for analyses. Large variations in administration of neo-RT and neo-CRT were observed. Elderly patients less often received neo-RT and neo-CRT. Patients with stage III disease received neo-CRT more frequently than neo-RT. Administration of neo-RT versus surgery without neoadjuvant treatment was significantly associated with improved survival in The Netherlands (HR, 0.62; 95% confidence interval [CI], 0.53-0.73) as well as in Sweden (HR, 0.79; 95% CI, 0.69-0.90). Administration of neo-CRT was associated with enhanced survival in The Netherlands (HR, 0.62; 95% CI, 0.50-0.78) but not in Sweden (HR, 0.97; 95% CI, 0.80-1.18). The mortality of patients treated with neo-CRT compared with neo-RT showed inconsistent results in population-based centers. Conclusions Our results support an association of neo-RT with enhanced survival among stage II and III rectal cancer patients. Comparing neo-CRT with neo-RT, larger variations and inconsistent results with respect to survival were observed across centers.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID-metabolizing enzymes central to NSAID metabolism including UDP-glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three-SNP genotype in UGT1A6 (G-A-A; Ala7-Thr181-Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04-14.45 and OR 1.34; 95% CI 1.10-1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P-interaction = 0.02), a three-SNP genotype within UGT2B4 and ibuprofen use (P-interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P-interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.

Colorectal cancer is a leading cause of morbidity and mortality worldwide in both men and women. The gut microbiome is increasingly recognized as having an important role in human health and disease. Fusobacterium has been identified in former studies as a leading gut bacterium associated with colorectal cancer, but it is still not clear if it plays an oncogenic role. In the current study, fecal samples were collected prior to bowel preparation from participants of screening colonoscopy in the German BliTz study. Using 16S rRNA gene analysis, we examined the presence and relative abundance of Fusobacterium in fecal samples from 500 participants, including 46, 113, 110 and 231 individuals with colorectal cancer, advanced adenomas, non-advanced adenomas and without any neoplasms, respectively. We found that the abundance of Fusobacterium in feces was strongly associated with the presence of colorectal cancer (P-value < 0.0001). This was confirmed by PCR at the species level for Fusobacterium nucleatum. However, no association was seen with the presence of advanced adenomas (P-value = 0.80) or non-advanced adenomas (P-value = 0.80), nor were there any associations observed with dietary or lifestyle habits. Although a causal role cannot be ruled out, our observations, based on fecal microbiome, support the hypothesis that Fusobacterium is a passenger that multiplies in the more favorable conditions caused by the malignant tumor rather than a causal factor in colorectal cancer development.

Epigenome-wide association studies have established methylation patterns related to smoking, the major risk factor of lung cancer (LC), which are distinct from methylation profiles disclosed in LC patients. This study simultaneously investigated associations of smoking-associated and LC-related methylation markers with LC mortality. DNA methylation was determined by HM450K assay in baseline blood samples of 1,565 older adults in a population-based case-cohort study. The associations of 151 smoking-associated CpGs (smoCpGs) and 3,806 LC-related CpGs (caCpGs) with LC mortality were assessed by weighted Cox regression models, controlling for potential confounders. Multi-loci methylation scores were separately constructed based on smoCpGs and caCpGs. During a median follow-up of 13.8 years, 60 participants who had a first diagnosis of LC died from LC. The average time between sample collection and LC diagnosis was 5.8 years. Hypomethylation at 77 smoCpGs and 121 caCpGs, and hypermethylation at 4 smoCpGs and 66 caCpGs were associated with LC mortality. The associations were much stronger for smoCpGs than for caCpGs. Hazard ratios (95% CI) were 7.82 (2.91-21.00) and 2.27 (0.75-6.85), respectively, for participants in highest quartile of Score I (based on 81 smoCpGs) and Score II (based on 187 caCpGs), compared with participants in the corresponding lower three quartiles. Score I outperformed Score II, with an optimism-corrected C-index of 0.87 vs. 0.77. In conclusion, although methylation changes of both smoking-associated and LC-related genes are associated with LC mortality, only smoking-associated methylation markers predict LC mortality with high accuracy, and may thus serve as promising candidates to identify high risk populations for LC screening.

Minimally invasive surgery (MIS) of colorectal cancer (CRC) was first introduced over 20 years ago and recently has gained increasing acceptance and usage beyond clinical trials. However, data on dissemination of the method across countries and on long-term outcomes are still sparse. In the context of a European collaborative study, a total of 112,023 CRC cases from 3 population-based (N=109,695) and 4 institute-based clinical cancer registries (N=2328) were studied and compared on the utilization of MIS versus open surgery. Cox regression models were applied to study associations between surgery type and survival of patients from the population-based registries. The study considered adjustment for potential confounders. The percentage of CRC patients undergoing MIS differed substantially between centers and generally increased over time. MIS was significantly less often used in stage II to IV colon cancer compared with stage I in most centers. MIS tended to be less often used in older (70+) than in younger colon cancer patients. MIS tended to be more often used in women than in men with rectal cancer. MIS was associated with significantly reduced mortality among colon cancer patients in the Netherlands (hazard ratio [HR] 0.66, 95% confidence interval [CI] (0.63-0.69), Sweden (HR 0.68, 95% CI 0.60-0.76), and Norway (HR 0.73, 95% CI 0.67-0.79). Likewise, MIS was associated with reduced mortality of rectal cancer patients in the Netherlands (HR 0.74, 95% CI 0.68-0.80) and Sweden (HR 0.77, 95% CI 0.66-0.90). Utilization of MIS in CRC resection is increasing, but large variation between European countries and clinical centers prevails. Our results support association of MIS with substantially enhanced survival among colon cancer patients. Further studies controlling for selection bias and residual confounding are needed to establish role of MIS in survival of patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Summary The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non-HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non-HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat-shock protein 70-hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non-HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.

BACKGROUND & AIMS: The presence of specific single nucleotide polymorphisms (SNPs) can be used to calculate an individual’s risk for colorectal cancer (CRC), called a genetic risk score (GRS). We investigated whether GRS can identify individuals with clinically relevant neoplasms in a screening colonoscopy population. METHODS: We derived a GRS based on 48 SNPs associated with CRC, identified in a comprehensive literature search. We obtained genetic data from 1043 participants (50–79 years old) in a screening colonoscopy study in Germany, recruited from 2005 through 2013 (294 with advanced neoplasms, 249 with non-advanced adenomas, and 500 without neoplasms). Each participant was assigned a GRS by aggregating their risk alleles (0, 1, or 2). Risk of advanced neoplasms and non-advanced adenoma according to GRS was calculated by multiple logistic regression. Risk advancement periods were calculated. We replicated our findings using data from a subset of the Tennessee Colorectal Polyp Study. RESULTS: An increased GRS was associated with higher prevalence of advanced neoplasms, but not non-advanced adenomas. Participants in the middle and upper tertile of GRSs had a 2.2-fold and 2.7-fold increase in risk, respectively, of advanced neoplasms compared to those in the lower tertile. Adjusted odds ratios (ORs) were 1.09 (95% CI, 0.76–1.57) for non-advanced adenoma in the middle tertile and 1.05 (95% CI, 0.70–1.55) for non-advanced adenoma in the upper tertile. The ORs were largest for proximal advanced neoplasms for participants in the middle tertile (OR, 3.55; 95% CI 1.85–6.82) and the upper tertile (OR, 3.61; 95% CI 1.84–7.10). The risk advancement period for medium vs low GRS was 13.4 years (95% CI 4.8–22.0) and for high vs low GRS was 17.5 years (95% CI, 7.8–27.3). CONCLUSIONS: In a genetic analysis of participants in a CRC screening study in Germany, an increased GRS (based on CRC-associated SNPs) was associated with increased prevalence of advanced neoplasms. These findings might be used in defining risk-adapted screening ages.

e16251Background: Literature-recorded survival for overall pancreatic cancer (PaC) patients is dismal. This is the first international large-scale population-based study aiming at providing detaile...

4127Background: The role of chemotherapy in the treatment of pancreatic cancer (PaC) has been well-established, while radiation plays ambiguous roles. This large-scale international population-base...

Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II-IV) (hazard ratio (HR)=2.23, 95% confidence interval (95% CI): 1.21-4.10, P=0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR=2.37, 95% CI: 1.16-4.84, P=0.018) and in HLA-Bw4(-) (HR=3.20, 95% CI: 1.35-7.60, P=0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II-IV) (HR=0.24, 95% CI: 0.07-0.85, P=0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.

Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.

Oxaliplatin-based chemotherapy exerts its effects through generating DNA damage. Hence, genetic variants in DNA repair pathways could modulate treatment response. We used a prospective cohort of 623 colorectal cancer patients with stage II-IV disease treated with adjuvant/palliative chemotherapy to comprehensively investigate 1727 genetic variants in the DNA repair pathways as potential predictive markers for oxaliplatin treatment. Single nucleotide polymorphisms (SNP) associations with overall survival and recurrence-free survival were assessed using a Cox regression model. Pathway analysis was performed using the gamma method. Patients carrying variant alleles of rs3783819 (MNAT1) and rs1043953 (XPC) experienced a longer overall survival after treatment with oxaliplatin than patients who did not carry the variant allele, while the opposite association was found in patients who were not treated with oxaliplatin (false discovery rate-adjusted P-values for heterogeneity 0.0047 and 0.0237, respectively). The nucleotide excision repair (NER) pathway was found to be most likely associated with overall survival in patients who received oxaliplatin (P-value=0.002). Our data show that genetic variants in the NER pathway are potentially predictive of treatment response to oxaliplatin.