We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

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There is a wide variability in cytosolic HA levels in colorectal carcinomas, which seems to be related to the biological heterogeneity of these tumours. In addition, high tumour cytosolic HA levels were associated with an unfavourable outcome in patients with resectable colorectal cancer. HA may provide additional information to that given by other biochemical markers currently used in colorectal cancer.

Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Background: Genome-wide association studies have identified over 170 common breast cancer susceptibility variants, many of them with differential associations by estrogen receptor (ER).How these variants are related to other tumor features is unclear.Methods: Analyses included 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 178 genotyped or imputed single nucleotide polymorphisms (SNPs). We used two-stage polytomous logistic regression models to evaluate SNPs in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.Results: Nearly half of the SNPs (85 of 178) were associated with at least one tumor feature (false discovery rate <5%). Case-case comparisons identified ER and grade as the most common heterogeneity sources, followed by PR and HER2. Case-control comparisons among these 85 SNPs with intrinsic-like subtypes identified 65 SNPs strongly or exclusively associated at P<0.05 with luminal-like subtypes, 5 SNPs associated with all subtypes at differing strengths, and 15 SNPs primarily associated with non-luminal tumors, especially triple-negative (TN) disease. The I157T CHEK2 variant (rs17879961) was associated in opposite directions with luminal A-like (odds ratio (OR; 95% confidence interval (CI))=1.44 (1.31 to 1.59); P=9.26x10 -14 ) and TN (OR (95% CI)=0.61 (0.47 to 0.80); P=2.55x10 -4 ). Conclusion:About half of the breast cancer susceptibility loci discovered in overall and ERspecific risk analyses have differential associations with clinical tumor features. These findings provide insights into the genetic predisposition of breast cancer subtypes and can inform subtype-specific risk prediction.