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Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants., Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants., Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022., Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years., Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%)., Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Differentially methylated CpG sites (dmCpGs) that distinguish prostate tumour from adjacent benign tissue could aid in the diagnosis and prognosis of prostate cancer. Previously, the identification of such dmCpGs has only been undertaken in radical prostatectomy (RP) samples and not primary diagnostic tumour samples (needle biopsy or transurethral resection of the prostate). We interrogated an Australian dataset comprising 125 tumour and 43 adjacent histologically benign diagnostic tissue samples, including 41 paired samples, using the Infinium Human Methylation450 BeadChip. Regression analyses of paired tumour and adjacent benign samples identified 2,386 significant dmCpGs (Bonferroni p < 0.01; delta-β ≥ 40%), with LASSO regression selecting 16 dmCpGs that distinguished tumour samples in the full Australian diagnostic dataset (AUC = 0.99). Results were validated in independent North American (n paired  = 19; AUC = 0.87) and The Cancer Genome Atlas (TCGA; n paired  = 50; AUC = 0.94) RP datasets. Two of the 16 dmCpGs were in genes that were significantly down-regulated in Australian tumour samples (Bonferroni p < 0.01; GSTM2 and PRKCB). Ten additional dmCpGs distinguished low (n = 34) and high Gleason (n = 88) score tumours in the diagnostic Australian dataset (AUC = 0.95), but these performed poorly when applied to the RP datasets (North American: AUC = 0.66; TCGA: AUC = 0.62). The DNA methylation marks identified here could augment and improve current diagnostic tests and/or form the basis of future prognostic tests., (© 2024. The Author(s).)

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers., (© 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that (a) for breast cancer diagnosed at a young age, for example, <50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS-disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first-degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal., (© 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

Background: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus., Methods: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants., Results: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%)., Conclusion: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins., Impact: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens., (©2023 American Association for Cancer Research.)