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Miguel Angel Luque-Fernandez is supported by a Miguel Servet I Investigator award (Grant CP17/00206) and a project grant EU-FEDER-FIS PI-18/01593 from the Instituto de Salud Carlos III, Madrid, Spain. Danilo Alvares is supported by the National Fund for Scientific and Technological Development (FONDECYT, Chile) grant number 11190018., Cancer survival represents one of the main indicators of interest in cancer epidemiology. However, the survival of cancer patients can be affected by several factors, such as comorbidities, that may interact with the cancer biology. Moreover, it is interesting to understand how different cancer sites and tumour stages are affected by different comorbidities. Identifying the comorbidities that affect cancer survival is thus of interest as it can be used to identify factors driving the survival of cancer patients. This information can also be used to identify vulnerable groups of patients with comorbidities that may lead to worst prognosis of cancer. We address these questions and propose a principled selection and evaluation of the effect of comorbidities on the overall survival of cancer patients. In the first step, we apply a Bayesian variable selection method that can be used to identify the comorbidities that predict overall survival. In the second step, we build a general Bayesian survival model that accounts for time-varying effects. In the third step, we derive several posterior predictive measures to quantify the effect of individual comorbidities on the population overall survival. We present applications to data on lung and colorectal cancers from two Spanish population-based cancer registries. The proposed methodology is implemented with a combination of the R-packages mombf and rstan. We provide the code for reproducibility at https://github.com/migariane/ BayesVarImpComorbiCancer., Miguel Servet I Investigator award CP17/00206 EU-FEDER-FIS PI-18/01593, Instituto de Salud Carlos III, Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 11190018

Background Numerous studies have analysed the effect of comorbidity on cancer outcomes, but evidence on the association between multimorbidity and short-term mortality among colorectal cancer patients is limited. We aimed to assess this association and the most frequent patterns of multimorbidity associated with a higher short-term mortality risk among colorectal cancer patients in Spain. Methods Data were obtained from two Spanish population-based cancer registries and electronic health records. We estimated the unadjusted cumulative incidence of death by comorbidity status at 6 months and 1 year. We used a flexible parametric model to derive the excess mortality hazard ratios (HRs) for multimorbidity after adjusting for sex, age at diagnosis, cancer stage and treatment. We estimated the adjusted cumulative incidence of death by comorbidity status and identified multimorbidity patterns. Results Among the study participants, 1,048 cases were diagnosed with cancers of the colon and rectum, 2 cases with cancer of the anus with overlapping sites of the rectum and 11 cases with anal adenocarcinomas but treated as colorectal cancer patients. Among 1,061 colorectal cancer patients, 171 (16.2%) died before 6 months, 246 (23.3%) died before the 1-year follow-up, and 324 (30.5%) had multimorbidity. Patients with multimorbidity had two times higher mortality risk than those without comorbidities at 6 months (adjusted HR: 2.04; 95% confidence interval [CI]: 1.30–3.20, p = 0.002). The most frequent multimorbidity pattern was congestive heart failure + diabetes. However, patients with rheumatologic disease + diabetes had two times higher 1-year mortality risk than those without comorbidities (HR: 2.23; 95% CI: 1.23–4.07, p = 0.008). Conclusions Multimorbidity was a strong independent predictor of short-term mortality at 6 months and 1 year among the colorectal cancer patients in Spain. The identified multimorbidity pattern was consistent. Our findings might help identify patients at a higher risk for poor cancer and treatment outcomes M.A.L.F. received support from the Instituto de Salud Carlos III, Madrid, Spain (grant/award no. CP17/ 00206-EU-FEDER), and M.J.S. received support from the Andalusian Department of Health (grant no. PI0152/2017)

Colorectal cancer (CRC) is the third most common cancer worldwide. It has also been demonstrated that over the last ten years the incidence of CRC among younger people below the age of 50 is also increasing. Screening for colorectal cancer is of utmost importance; the rationale behind screening is to target the malignancy and reduce the incidence and mortality of the disease. Diagnostic methods to screen for incidence or relapse are therefore a requisite to detect cancer as early as possible. Scientific findings demonstrate that many deaths are due to lack of screening and therefore early identification will lead to greater survivability. In colorectal cancer, diagnostic tests include liquid biopsy biomarkers. Since the discovery of microRNAs (miRNAs), many studies have demonstrated the relationship between miRNAs and the various sub-types of CRC. Several miRNAs have been identified after analysing serum or plasma samples in patients, and such miRNAs were found to be significantly dysregulated. Such findings place the possibility of miRNAs to be at the epicentre of novel diagnostic techniques for CRC identification and sub-type stratification, including other characteristics associated with CRC development such as patient prognosis. The following review serves to underline the latest findings for miRNAs with such potential for routine diagnostic employment in CRC diagnostics and treatments., peer-reviewed

Introduction Colorectal cancer treatment requires a complex, multidisciplinary approach. Because of the potential variability, monitoring through clinical audits is advisable. This study assesses the effects of a quality improvement action plan in patients with locally advanced rectal cancer and treated with radiotherapy. Methods Comparative, multicentre study in two cohorts of 120 patients each, selected randomly from patients diagnosed with rectal cancer who had initiated radiotherapy with a curative intent. Based on the results from a baseline clinical audit in 2013, a quality improvement action plan was designed and implemented; a second audit in 2017 evaluated its impact. Results Standardised information was present on 77.5% of the magnetic resonance imaging (MRI) staging reports. Treatment strategies were similar in all three study centres. Of the patients whose treatment was interrupted, just 9.7% received a compensation dose. There was an increase in MRI re-staging from 32.5 to 61.5%, and a significant decrease in unreported circumferential resection margins following neoadjuvant therapy (ypCRM), from 34.5 to 5.6% (p Conclusions The comparison between two clinical audits showed improvements in neoadjuvant radiotherapy in rectal cancer patients. Some indicators reveal areas in need of additional efforts, for example to reduce the overall treatment time.

Guidelines recommend routine screening for colorectal cancer (CRC) in asymptomatic adults starting at age 50. The most extensively used noninvasive test for CRC screening is the fecal immunochemical test (FIT), which has an overall sensitivity for CRC of approximately 61.0%-91.0%, which drops to 27.0%-67.0% for advanced adenomas. These figures contain a high false-positive rate and a low positive predictive value. This work aimed to develop a new, noninvasive CRC screening tool based on fecal bacterial markers capable of decreasing FIT false-positive rates in a FIT-positive population. We defined a fecal bacterial signature (RAID-CRC Screen) in a proof-of-concept with 172 FIT-positive individuals and validated the obtained results on an external cohort of 327 FIT-positive subjects. All study participants had joined the national CRC screening program. In the clinical validation of RAID-CRC Screen, a sensitivity of 83.9% and a specificity of 16.3% were obtained for the detection of advanced neoplasm lesions (advanced adenomas and/or CRC). FIT 20 μg/g produced 184 false-positive results. Using RAID-CRC Screen, this value was reduced to 154, thus reducing the false-positive rate by 16.3%. The RAID-CRC Screen test could be implemented in CRC screening programs to allow a significant reduction in the number of colonoscopies performed unnecessarily for FIT-positive participants of CRC screening programs JGG, XA, MSP, MS SRP, JA, LO, MM are employees from GoodGut, a company that has received private and public funding: RTC-2016-5017-1 (Spanish Ministry of Economy, Industry and Competitivity (MINECO)); SNEO-20151529 (Neotec)

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas Tis study was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds- a way to build Europe, [SAF2016-80888-R (LV), SAF2015-68016-R (GC), Formación de Personal Investigador (IQ)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234, PI16/00563 (CL), Sara Borrell postdoctoral contract (PM)], the Government of Catalonia [Department of Health PERIS SLT002/16/0037, SLT002/16/00164 “Acció instrumental d’incorporació de científcs i tecnòlegs” (MT)], AGAUR 2017SGR1282 and CERCA Program] and Fundación Olga Torres. Tis study has been enabled by COST Action CA17118

Inflammation and antioxidant capacity have been associated with colorectal and breast cancer. We computed the dietary inflammatory index (DII&reg, ), and the total dietary non-enzymatic antioxidant capacity (NEAC) and associated them with colorectal and breast cancer risk in the population-based multi case-control study in Spain (MCC-Spain). We included 1852 colorectal cancer and 1567 breast cancer cases, and 3447 and 1486 population controls, respectively. DII score and NEAC were derived using data from a semi-quantitative validated food frequency questionnaire. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for energy-adjusted DII (E-DII), and a score combining E-DII and NEAC. E-DII was associated with colorectal cancer risk (OR = 1.93, highest quartile versus lowest, 95%CI:1.60&ndash, 2.32, p-trend: &lt, 0.001), this increase was observed for both colon and rectal cancer. Less pronounced increased risks were observed for breast cancer (OR = 1.22, highest quartile versus lowest, 95%CI:0.99&ndash, 1.52, p-trend: &gt, 0.10). The combined score of high E-DII scores and low antioxidant values were associated with colorectal cancer risk (OR = 1.48, highest quartile versus lowest, 95%CI: 1.26&ndash, 1.74, 0.001), but not breast cancer. This study provides evidence that a pro-inflammatory diet is associated with increased colorectal cancer risk while findings for breast cancer were less consistent.

Colorectal cancer (CRC) is the third most common cancer worldwide. Population-based, high-resolution studies are essential for the continuous evaluation and updating of diagnosis and treatment standards. This study aimed to assess adherence to clinical practice guidelines and investigate its relationship with survival. We conducted a retrospective high-resolution population-based study of 1050 incident CRC cases from the cancer registries of Granada and Girona, with a 5-year follow-up. We recorded clinical, diagnostic, and treatment-related information and assessed adherence to nine quality indicators of the relevant CRC guidelines. Overall adherence (on at least 75% of the indicators) significantly reduced the excess risk of death (RER) = 0.35 [95% confidence interval (CI) 0.28&ndash, 0.45]. Analysis of the separate indicators showed that patients for whom complementary imaging tests were requested had better survival, RER = 0.58 [95% CI 0.46&ndash, 0.73], as did patients with stage III colon cancer who underwent adjuvant chemotherapy, RER = 0.33, [95% CI 0.16&ndash, 0.70]. Adherence to clinical practice guidelines can reduce the excess risk of dying from CRC by 65% [95% CI 55&ndash, 72%]. Ordering complementary imagining tests that improve staging and treatment choice for all CRC patients and adjuvant chemotherapy for stage III colon cancer patients could be especially important. In contrast, controlled delays in starting some treatments appear not to decrease survival.

KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth. NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRASQ61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors.

Background: Faecalibacterium prausnitzii comprises 2 phylogroups, whose abundance in healthy and diseased gut and in conjunction with Escherichia coli has not yet been studied. This work aims to determine the contribution of F. prausnitzii phylogroups I and II in intestinal disease and to assess their potential diagnostic usefulness as biomarkers for gut diseases. Methods: Total F. prausnitzii, its phylogroups, and E. coli loads were determined by quantitative polymerase chain reaction targeting the 16S rRNA gene on biopsies from 31 healthy controls (H), 45 patients with Crohn's disease (CD), 25 patients with ulcerative colitis, 10 patients with irritable bowel syndrome, and 20 patients with colorectal cancer. Data were normalized to total bacterial counts and analyzed according to patients' disease location and clinical characteristics. Results: Lower levels of both total F. prausnitzii and phylogroup I were found in subjects with CD, ulcerative colitis, and colorectal cancer (P < 0.001) compared with H subjects. Phylogroup I load was a better biomarker than total F. prausnitzii to discriminate subjects with gut disorders from H. Phylogroup II depletion was observed only in patients with CD (P < 0.001) and can be potentially applied to differentiate ulcerative pancolitis from colonic CD. No statistically significant correlation between E. coli and any of the 2 F. prausnitzii phylogroups was found in any group of patients or by inflammatory bowel disease location. Phylogroup I was lower in active patients with CD, whereas those CD with intestinal resection showed a reduction in phylogroup II. Treatments with mesalazine and immunosuppressants did not result in the recovery of F. prausnitzii phylogroups abundance. Conclusions: F. prausnitzii phylogroup I was depleted in CD, ulcerative colitis, and colorectal cancer, whereas phylogroup II was specifically reduced in CD. Quantification of F. prausnitzii phylogroups and E. coli may help to identify gut disorders and to classify inflammatory bowel disease location.

Background: Risk prediction models for colorectal cancer (CRC) detection in symptomatic patients based on available biomarkers may improve CRC diagnosis. Our aim was to develop, compare with the NICE referral criteria and externally validate a CRC prediction model, COLONPREDICT, based on clinical and laboratory variables. Methods: This prospective cross-sectional study included consecutive patients with gastrointestinal symptoms referred for colonoscopy between March 2012 and September 2013 in a derivation cohort and between March 2014 and March 2015 in a validation cohort. In the derivation cohort, we assessed symptoms and the NICE referral criteria, and determined levels of faecal haemoglobin and calprotectin, blood haemoglobin, and serum carcinoembryonic antigen before performing an anorectal examination and a colonoscopy. A multivariate logistic regression analysis was used to develop the model with diagnostic accuracy with CRC detection as the main outcome. Results: We included 1572 patients in the derivation cohort and 1481 in the validation cohorts, with a 13.6 % and 9. 1 % CRC prevalence respectively. The final prediction model included 11 variables: age (years) (odds ratio [OR] 1.04, 95 % confidence interval [CI] 1.02-1.06), male gender (OR 2.2, 95 % CI 1.5-3.4), faecal haemoglobin >= 20 mu g/g (OR 17.0, 95 % CI 10.0-28.6), blood haemoglobin = 3 ng/mL (OR 4.5, 95 % CI 3.0-6.8), acetylsalicylic acid treatment (OR 0.4, 95 % CI 0.2-0.7), previous colonoscopy (OR 0.1, 95 % CI 0.06-0.2), rectal mass (OR 14.8, 95 % CI 5.3-41.0), benign anorectal lesion (OR 0.3, 95 % CI 0.2-0.4), rectal bleeding (OR 2.2, 95 % CI 1.4-3.4) and change in bowel habit (OR 1.7, 95 % CI 1.1-2.5). The area under the curve (AUC) was 0.92 (95 % CI 0.91-0.94), higher than the NICE referral criteria (AUC 0.59, 95 % CI 0.55-0.63; p < 0.001). On the basis of the thresholds with 90 % (5.6) and 99 % (3.5) sensitivity, we divided the derivation cohort into three risk groups for CRC detection: high (30.9 % of the cohort, positive predictive value [PPV] 40.7 %, 95 % CI 36.7-45.9 %), intermediate (29.5 %, PPV 4.4 %, 95 % CI 2.8-6.8 %) and low (39.5 %, PPV 0.2 %, 95 % CI 0.0-1.1 %). The discriminatory ability was equivalent in the validation cohort (AUC 0.92, 95 % CI 0.90-0.94; p = 0.7). Conclusions: COLONPREDICT is a highly accurate prediction model for CRC detection. This study was funded by a grant from Instituto de Salud Carlos III (PI11/00094). JC and VH have received an intensification grant through the European Commission funded "BIOCAPS" project (FP-7-REGPOT 2012-2013-1, Grant agreement no. FP7-316265). The validation cohort recruitment was funded by a grant from Fundacio de la Marato TV3 2012 (785/U/2013). The funding institutions had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

PI13-00285 PI11-01439 Germline mutations in UNC5C have been suggested to increase colorectal cancer (CRC) risk, thus causing hereditary CRC. However, the evidence gathered thus far is insufficient to include the study of the UNC5C gene in the routine genetic testing of familial CRC. Here we aim at providing a more conclusive answer about the contribution of germline UNC5C mutations to genetically unexplained hereditary CRC and/or polyposis cases. To achieve this goal we sequenced the coding region and exon-intron boundaries of UNC5C in 544 familial CRC or polyposis patients (529 families), using a technique that combines pooled DNA amplification and massively parallel sequencing. A total of eight novel or rare variants, all missense, were identified in eight families. Co-segregation data in the families and association results in case-control series are not consistent with a causal effect for 7 of the 8 identified variants, including c.1882_1883delinsAA (p.A628K), previously described as a disease-causing mutation. One variant, c.2210G > A (p.S737N), remained unclassified. In conclusion, our results suggest that the contribution of germline mutations in UNC5C to hereditary colorectal cancer and to polyposis cases is negligible. This work was funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds -a way to build Europe- [SAF2012-38885 (LV), SAF2013-45836-R (XSP), SAF2012-33636 (GC)]; Carlos III Health Institute [PI13-00285 (CL), PI11-01439 (VM)]; Red Tematica de Investigacion Cooperativa en Cancer [RTICC RD12/0036/0031, RD12/0036/0008, RD12/0036/0067], the Government of Catalonia [2014SGR338, 2014SGR647], and the Scientific Foundation Asociacion Espanola Contra el Cancer. We thank Tirso Pons from the Spanish National Cancer Research Center (CNIO) for his assistance. We are grateful to the researchers of the MCC-Spain study for providing the data to assess the identified UNC5C rare variants in the general population. Sí

The recent identification of HER2 gene amplification as a novel predictor of resistance to the EGFR (HER2)-targeted antibody cetuximab and of response to combination therapies against EGFR and HER2 in wild-type KRAS tumor settings may represent a further step toward personalized medicine for patients with colorectal cancer. Herein, we show that transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification is a molecular phenomenon that takes place in EGFR-dependent, wild-type KRAS squamous cell carcinoma (SCC) cells that acquire resistance to cetuximab. Since cetuximab activity against cetuximab-refractory SCC cells can be fully restored in the presence of the anti-HER2 monoclonal antibody trastuzumab, our findings suggest that, beyond HER2 gene amplification, we might need to redefine the threshold values for HER2 positivity to improve the accuracy of the selection of cetuximab-refractory patients with wild-type KRAS that may benefit from receiving a cetuximab/trastuzumab combination.