Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse ...summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
Associations of coffee consumption with cancer mortality are inconsistent for many types of cancer, and confounding by smoking is an important concern.
Cox proportional hazards regression was used to ...estimate multivariable-adjusted HRs for coffee consumption associated with death from all cancers combined and from specific cancer types among 922,896 Cancer Prevention Study-II participants ages 28-94 years who completed a four-page questionnaire and were cancer free at baseline in 1982.
During follow-up through 2012, there were 118,738 cancer-related deaths. There was a nonlinear association between coffee consumption and all-cancer death among current smokers and former smokers and no association among never smokers. Among nonsmokers, a 2 cup/day increase in coffee consumption was inversely associated with death from colorectal HR = 0.97; 95% confidence interval (CI) 0.95-0.99, liver HR = 0.92; 95% CI, 0.88-0.96, and female breast (HR = 0.97; 95% CI, 0.94-0.99) cancers, and positively associated with esophageal cancer-related death (HR = 1.07; 95% CI, 1.02-1.12). For head and neck cancer, a nonlinear inverse association was observed starting at 2-3 cups per day (HR = 0.72; 95% CI, 0.55-0.95), with similar associations observed at higher levels of consumption.
These findings are consistent with many other studies that suggest coffee drinking is associated with a lower risk of colorectal, liver, female breast, and head and neck cancer. The association of coffee consumption with higher risk of esophageal cancer among nonsmokers in our study should be confirmed.
These results underscore the importance of assessing associations between coffee consumption and cancer mortality by smoking status.
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Persisters are the minor subpopulation of bacterial cells that lack alleles conferring resistance to a specific bactericidal antibiotic but can survive otherwise lethal concentrations of that ...antibiotic. In infections with Mycobacterium tuberculosis, such persisters underlie the need for long-term antibiotic therapy and contribute to treatment failure in tuberculosis cases. Here, we demonstrate the value of dual-reporter mycobacteriophages (Φ
DRMs) for characterizing M. tuberculosis persisters. The addition of isoniazid (INH) to exponentially growing M. tuberculosis cells consistently resulted in a 2- to 3-log decrease in CFU within 4 days, and the remaining ≤1% of cells, which survived despite being INH sensitive, were INH-tolerant persisters with a distinct transcriptional profile. We fused the promoters of several genes upregulated in persisters to the red fluorescent protein tdTomato gene in Φ
GFP10, a mycobacteriophage constitutively expressing green fluorescent protein (GFP), thus generating Φ
DRMs. A population enriched in INH persisters exhibited strong red fluorescence, by microscopy and flow cytometry, using a Φ
DRM with tdTomato controlled from the dnaK promoter. Interestingly, we demonstrated that, prior to INH exposure, a population primed for persistence existed in M. tuberculosis cells from both cultures and human sputa and that this population was highly enriched following INH exposure. We conclude that Φ
DRMs provide a new tool to identify and quantitate M. tuberculosis persister cells.
Tuberculosis (TB) is again the leading cause of death from a single infectious disease, having surpassed HIV. The recalcitrance of the TB pandemic is largely due to the ability of the pathogen Mycobacterium tuberculosis to enter a persistent state in which it is less susceptible to antibiotics and immune effectors, necessitating lengthy treatment. It has been difficult to study persister cells, as we have lacked tools to isolate these rare cells. In this article, we describe the development of dual-reporter mycobacteriophages that encode a green fluorescent marker of viability and in which the promoters of genes we have identified as induced in the persister state are fused to a gene encoding a red fluorescent protein. We show that these tools can identify heterogeneity in a cell population that correlates with propensity to survive antibiotic treatment and that the proportions of these subpopulations change in M. tuberculosis cells within human sputum during the course of treatment.
Smoking is an established risk factor for pancreatic cancer; however, detailed examination of the association of smoking intensity, smoking duration, and cumulative smoking dose with pancreatic ...cancer is limited. The authors analyzed pooled data from the international Pancreatic Cancer Cohort Consortium nested case-control study (1,481 cases, 1,539 controls). Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Smoking intensity effects were examined with an excess odds ratio model that was linear in pack-years and exponential in cigarettes smoked per day and its square. When compared with never smokers, current smokers had a significantly elevated risk (odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.38, 2.26). Risk increased significantly with greater intensity (≥30 cigarettes/day: OR = 1.75, 95% CI: 1.27, 2.42), duration (≥50 years: OR = 2.13, 95% CI: 1.25, 3.62), and cumulative smoking dose (≥40 pack-years: OR = 1.78, 95% CI: 1.35, 2.34). Risk more than 15 years after smoking cessation was similar to that for never smokers. Estimates of excess odds ratio per pack-year declined with increasing intensity, suggesting greater risk for total exposure delivered at lower intensity for longer duration than for higher intensity for shorter duration. This finding and the decline in risk after smoking cessation suggest that smoking has a late-stage effect on pancreatic carcinogenesis.
This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.
A total of 26,798 ...non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in
,
,
,
,
,
,
,
, and
. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC.
The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of
,
, and
carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of
and
carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk.
PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of
and nearly half of
carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.
While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited evidence for an association between consumption of lycopene and tomato ...products and prostate‐cancer specific mortality (PCSM). We examined the associations of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with PCSM in a large prospective cohort. This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992 or 1993 and June 2011. Prediagnosis dietary data, collected at baseline, were available for 8,898 men, of whom 526 died of prostate cancer through 2012. Postdiagnosis dietary data, collected on follow‐up surveys in 1999 and/or 2003, were available for 5,643 men, of whom 363 died of prostate cancer through 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PCSM. Neither prediagnosis nor postdiagnosis dietary lycopene intake was associated with PCSM (fourth vs. first quartile HR = 1.00, 95% CI 0.78–1.28; HR = 1.22, 95% CI 0.91–1.64, respectively). Similarly, neither prediagnosis nor postdiagnosis consumption of tomato products was associated with PCSM. Among men with high‐risk cancers (T3–T4 or Gleason score 8–10, or nodal involvement), consistently reporting lycopene intake ≥ median on both postdiagnosis surveys was associated with lower PCSM (HR = 0.41, 95% CI 0.17–0.99, based on ten PCSM cases consistently ≥ median intake) compared to consistently reporting intake < median. Future studies are needed to confirm the potential inverse association of consistently high lycopene intake with PCSM among men with high‐risk prostate cancers.
What's new?
While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited evidence for an association between their consumption and prostate‐cancer specific mortality (PCSM). This is the first study to comprehensively examine the associations of pre‐ and post‐diagnosis lycopene and tomato product intake with PCSM among men with nonmetastatic prostate cancer. No association was observed between pre‐ or post‐diagnosis intake and PCSM using a single dietary measurement. However, consistently high intake of lycopene after diagnosis assessed using repeated dietary questionnaires was associated with significantly lower risk of PCSM among men diagnosed with high‐risk prostate cancer.
Background Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%–20% of colorectal tumors display microsatellite instability ...(MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status. Methods The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (≥30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided. Results Recent BMI, modeled in 5 kg/m2 increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m2, was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31). Conclusion The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.
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