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Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P =.565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate β: −0.002, 95% CI = −0.008 to 0.004, P =.543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders.

Background/objective: Epidemiological and phenotypic differences exist in breast and ovarian cancers among patients of different ethnicity. Reasons for this are unclear and likely multifactorial. In Asian countries breast and ovarian cancers occur a decade earlier (1). In India, 15% of breast and ovarian cancer is diagnosed in patients over 65 years compared to approximately 50% in the UK, despite an increased UK incidence(1). Triple negative breast cancer is also more prevalent in India(1). A recent systematic review by our group examined the prevalence and spectra of BRCA1/2 mutations in the Indian population and concluded that there is a lack of high-quality genetic and histopathology data (2). This study examines BRCA mutation prevalence, spectra, and clinico-pathological features of breast and ovarian cancers in patients of Asian origin with familial risk. Methods: 89 patients of Asian origin were identified out of a total of 3359 patients referred to the regional genetics service for BRCA1/2 testing between 2006-2016. Genetics data were correlated with recorded histopathological including the type of surgical excision, tumour type, size, grade and receptor status (breast cancers). Outcome data, where available, was also recorded. The BRCA1/2 genetic variants were searched in the ClinVar (3) and BIC (Breast cancer Information Core)databases (4) to confirm their pathogenicity. Results: 51 patients were of Indian (57.30%), 21 of Pakistani (23.59%) and 3 of Bangladeshi (3.37%) origin with the remaining 14 of other unspecified or mixed Asian ethnicities (15.73%). 25 BRCA variants across 21 patients were identified. 16.85% (n=15) had a pathogenic variant (BRCA1 n= 11, BRCA2 n= 4) and 11.23% (n=10) had a variant of unknown significance (VUS) (BRCA1 n=1, BRCA2 n=9). One BRCA1 variant (c.3770_3771delAG, p.Glu1257GlyfsX9) occurred in 2 different patients, both of Indian origin. The Genome Aggregation Database (gnomAD) allele frequency of this variant in the South Asian population is reported as 3.27e-5. Pathology data for one or more parameters was available for 78 patients (87.64%). The majority were breast cancers, with a median age of 39 years. 90.90% of the BRCA1 and BRCA2 pathogenic variant breast cancers (PVBC) were of no special type (n =10, total 11). 87.50% of BRCA1 PVBCs (n=7, total 8) were HER2/oestrogen receptor (ER) negative and 85.71% were grade 3 (n=6, total 7). 100% (n=4, total 4) of BRCA2 PVBCs were grade 3 and ER positive. Two patients with a BRCA2 PVBC were male. Conclusion: This study shows, for the first time, the real-time genetic and pathological correlation of BRCA status in breast and ovarian cancer patients of Asian origin with familial risk. The higher number of pathogenic BRCA1 alterations compared to BRCA2 as well as the higher number of BRCA2 VUS compared to BRCA1 VUS is consistent with our previous work of the Indian population(2). The BRCA1/2 histological and molecular features are consistent with profiles reported in the literature. The genetic makeup may explain, at least partly, the phenotypic and epidemiological breast and ovarian cancer differences observed within different ethnicities. References: 1. Sundar S et al. Harnessing genomics to improve outcomes for women with cancer in India: key priorities for research. Lancet Oncol. 2018 Feb;19(2):e102-e112 2. Sharma-Oates A et al. Heterogeneity of germline variants in high risk breast and ovarian cancer susceptibility genes in India. Precis. Clin. Med. 2018 Sept; 1(2):75-87. 3. Landrum MJ et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. 4. Breast Cancer Information Core. An Open Access On-Line Breast Cancer Mutation Database. https://research.nhgri.nih.gov/bic/ Citation Format: Aisling Longworth, Jonathan Hoffman, Archana Sharma-Oates, Kai-Ren Ong, Rachel Hart, Yvonne Wallis, Anna Considine, Pooja Dasani, Raji Ganesan, Ian Tomlinson, Sudha Sundar, Abeer Shaaban. Genetics and pathological correlation of BRCA status in patients of Asian origin diagnosed with breast or ovarian cancer; a UK Reference Genetics Laboratory Study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-13.

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p

Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. Results: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (rg = 0.13, P = 2 × 10−04) and a rg of 0.12 between WHR and BE/EA (P = 1 × 10−02). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (rg = 0.17, P = 1.2 × 10−03), and WHR and EA in males (rg = 0.18, P = 1.51 × 10−02). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10−03) and WHR and BE/EA risk variants (P = 2 × 10−02). Conclusions: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. Impact: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.Summary BoxWhat is already known on this topicRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomesNo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond ageQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRCWhat this study addsAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention