Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

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.

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction.

Rare pathogenic variants in known breast cancer-susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, and TP53 via gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of known susceptibility genes and other unidentified major genes and a normally distributed polygenic component. The proportion of familial variance explained by the six genes was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessive risk component with a combined genotype frequency of 1.7% (95% CI: 0.3%-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38%-95%) for homozygotes, which may reflect the combined effects of multiple variants acting in a recessive manner, and a polygenic variance of 1.27 (95% CI: 0.94%-1.65), which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer-susceptibility genes and improve disease-risk prediction, especially at a young age.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

Do age at diagnosis, tumour thickness and tumour site explain sex differences in melanoma survival? A causal mediation analysis using cancer registry data.

Women diagnosed with melanoma have better survival than men, but little is known about potential intervention targets to reduce this survival gap by sex. We conducted a population-based study using Victorian Cancer Registry data including 5833 women and 6780 men aged 15 to 70 years when diagnosed with first primary melanoma between 2007 and 2015. Deaths to the end of 2020 were identified through linkage to the Victorian and national death registries. We estimated the effect of age at diagnosis, tumour thickness and tumour site on reducing the melanoma-specific survival gap by sex (ie, interventional indirect effects [IIEs]) on risk difference (RD) scale. Compared to women, there were 211 (95% CI: 145-278) additional deaths per 10 000 in men within 5 years following diagnosis. We estimated that 44% of this gap would be reduced by a hypothetical intervention shifting the distribution of melanoma thickness in men to be the same as that observed for women (IIEthickness RD 93 [95% CI: 75-118] per 10 000) and 20% by an intervention on tumour site (head and neck/trunk vs upper limb/lower limb; IIEsite RD 42 [95% CI: 15-72] per 10 000), while an intervention on age at diagnosis would have a negligible effect. Tumour thickness, tumour site and age at diagnosis mediated 65% of the effect of sex on 5-year melanoma survival in Victoria. Of these factors, tumour thickness had the most considerable mediating effect, suggesting that effective promotion of earlier detection of melanoma in men could potentially nearly halve the gap in melanoma-specific survival by sex.

Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer.

BACKGROUND: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). METHODS: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. RESULTS: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). CONCLUSION: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium.

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

Methylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer.

Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Hypertensive conditions of pregnancy, preterm birth, and premenopausal breast cancer risk: a premenopausal breast cancer collaborative group analysis.

PURPOSE: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group. METHODS: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression. RESULTS: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56). CONCLUSION: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy.

Healthy lifestyle is associated with reduced cardiovascular disease, depression and mortality in people at elevated risk of sleep apnea.

We assessed: (1) the independent and joint association of obstructive sleep apnea risk and healthy lifestyle with common consequences (excessive daytime sleepiness, depression, cardiovascular disease and stroke) of obstructive sleep apnea; and (2) the effect of healthy lifestyle on survival in people with increased obstructive sleep apnea risk. Data from 13,694 adults (median age 46 years; 50% men) were used for cross-sectional and survival analyses (mortality over 15 years). A healthy lifestyle score with values from 0 (most unhealthy) to 5 (most healthy) was determined based on diet, alcohol intake, physical activity, smoking and body mass index. In the cross-sectional analysis, obstructive sleep apnea risk was positively associated with all chronic conditions and excessive daytime sleepiness in a dose-response manner (p for trend < 0.001). The healthy lifestyle was inversely associated with all chronic conditions (p for trend < 0.001) but not with excessive daytime sleepiness (p for trend = 0.379). Higher healthy lifestyle score was also associated with reduced odds of depression and cardiovascular disease. We found an inverse relationship between healthy lifestyle score with depression (p for trend < 0.001), cardiovascular disease (p for trend = 0.003) and stroke (p for trend = 0.025) among those who had high obstructive sleep apnea risk. In the survival analysis, we found an inverse association between healthy lifestyle and all-cause mortality for all categories of obstructive sleep apnea risk (moderate/high- and high-risk groups [p for trend < 0.001]). This study emphasises the crucial role of a healthy lifestyle in mitigating the effects of obstructive sleep apnea risk in individuals with an elevated obstructive sleep apnea risk.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.

BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Common variants in breast cancer risk loci predispose to distinct tumor subtypes.

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.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Alcohol intake trajectories during the life course and risk of alcohol-related cancer: A prospective cohort study.

We examined associations between sex-specific alcohol intake trajectories and alcohol-related cancer risk using data from 22 756 women and 15 701 men aged 40 to 69 years at baseline in the Melbourne Collaborative Cohort Study. Alcohol intake for 10-year periods from age 20 until the decade encompassing recruitment, calculated using recalled beverage-specific frequency and quantity, was used to estimate group-based sex-specific intake trajectories. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for primary invasive alcohol-related cancer (upper aerodigestive tract, breast, liver and colorectum). Three distinct alcohol intake trajectories for women (lifetime abstention, stable light, increasing moderate) and six for men (lifetime abstention, stable light, stable moderate, increasing heavy, early decreasing heavy, late decreasing heavy) were identified. 2303 incident alcohol-related cancers were diagnosed during 485 525 person-years in women and 789 during 303 218 person-years in men. For men, compared with lifetime abstention, heavy intake (mean ≥ 60 g/day) at age 20 to 39 followed by either an early (from age 40 to 49) (early decreasing heavy; HR = 1.75, 95% CI: 1.25-2.44) or late decrease (from age 60 to 69) (late decreasing heavy; HR = 1.94, 95% CI: 1.28-2.93), and moderate intake (mean <60 g/day) at age 20 to 39 increasing to heavy intake in middle-age (increasing heavy; HR = 1.45, 95% CI: 1.06-1.97) were associated with increased risk of alcohol-related cancer. For women, compared with lifetime abstention, increasing intake from age 20 (increasing moderate) was associated with increased alcohol-related cancer risk (HR = 1.25, 95% CI: 1.06-1.48). Similar associations were observed for colorectal (men) and breast cancer. Heavy drinking during early adulthood might increase cancer risk later in life.

Physical activity and glioma: a case-control study with follow-up for survival.

PURPOSE: High-grade disease accounts for ~ 70% of all glioma, and has a high mortality rate. Few modifiable exposures are known to be related to glioma risk or mortality. METHODS: We examined associations between lifetime physical activity and physical activity at different ages (15-18 years, 19-29 years, 30-39 years, last 10 years) with the risk of glioma diagnosis, using data from a hospital-based family case-control study (495 cases; 371 controls). We followed up cases over a median of 25 months to examine whether physical activity was associated with all-cause mortality. Physical activity and potential confounders were assessed by self-administered questionnaire. We examined associations between physical activity (metabolic equivalent [MET]-h/wk) and glioma risk using unconditional logistic regression and with all-cause mortality in cases using Cox regression. RESULTS: We noted a reduced risk of glioma for the highest (≥ 47 MET-h/wk) versus lowest (< 24 METh/wk) category of physical activity for lifetime activity (OR = 0.58, 95% CI: 0.38-0.89) and at 15-18 years (OR = 0.57, 95% CI: 0.39-0.83). We did not observe any association between physical activity and all-cause mortality (HR for lifetime physical activity = 0.91, 95% CI: 0.64-1.29). CONCLUSION: Our findings are consistent with previous research that suggested physical activity during adolescence might be protective against glioma. Engaging in physical activity during adolescence has many health benefits; this health behavior may also offer protection against glioma.

Independent evaluation of melanoma polygenic risk scores in UK and Australian prospective cohorts.

BACKGROUND: Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS-based risk prediction, particularly assessment of calibration (comparing predicted to observed risks). OBJECTIVES: To evaluate PRS-based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. METHODS: We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case-cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single-nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta-analysis (PRS68), 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. RESULTS: Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62-0·68] and MCCS (E/O = 0·63, 95% CI 0·56-0·72). For UKB, calibration was improved by PRS adjustment, with PRS50-adjusted risks E/O = 0·91, 95% CI 0·87-0·95. The discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07-0·10, P < 0·0001), and higher than for PRS45-adjusted risks (Δ area under the curve 0·02-0·04, P < 0·001). CONCLUSIONS: A PRS derived from a larger, more diverse meta-analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations.

Television viewing time and all-cause mortality: interactions with BMI, physical activity, smoking, and dietary factors.

BACKGROUND: Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. METHODS: Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: < 2 h/day, 2-3 h/day, > 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors. RESULTS: From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with < 2 h/day of TV time was 1.34 (1.16, 1.55) at 70 years, 1.14 (1.04, 1.23) at 80 years, and 0.95 (0.84, 1.06) at 90 years. The TV time/mortality relationship was more evident in participants who were physically inactive (compared with active; p for interaction < 0.01) or had a higher dietary inflammatory index score (compared with a lower score; p for interaction = 0.03). No interactions were detected between TV time and BMI, smoking, alcohol intake, nor soft-drink consumption (all p for interaction > 0.16). CONCLUSIONS: The relationship between TV time and all-cause mortality may change with age. It may also be more pronounced in those who are otherwise inactive or who have a pro-inflammatory diet.