Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease.

Recombination, together with mutation, is the ultimate source of genetic variation in populations. We leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing-over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P<10−245). We identify a 17 base pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of African-enriched alleles of PRDM9.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 [95% confidence interval (CI) 4.84–5.29] for men of European ancestry to 3.74 [95% CI 3.36–4.17] for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher [95% CI 2.14–2.22], and men of East Asian ancestry 0.73-times lower [95% CI 0.71–0.76], than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

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Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.

Lung cancer is associated with smoking and age, both of which are associated with comorbidity. We evaluated the impact of comorbidity on lung cancer survival. Data on 56 comorbidities were abstracted from the records of a cohort of 1,155 patients. Survival effects were evaluated with Cox regression (outcome crude death). The adjusted R 2 statistic was used to compare the survival variation explained by predictive variables. No comorbidity was observed in 11.7% of patients, while 54.3% had 3 or more (mean 2.97) comorbidities. In multivariate analysis, 19 comorbidities were associated with survival: HIV/AIDS, tuberculosis, previous metastatic cancer, thyroid/glandular diseases, electrolyte imbalance, anemia, other blood diseases, dementia, neurologic disease, congestive heart failure, COPD, asthma, pulmonary fibrosis, liver disease, gastrointestinal bleeding, renal disease, connective tissue disease, osteoporosis and peripheral vascular disease. Only the latter was protective. Some of the hazards of comorbidities were explained by more directly acting comorbidities and/or receipt of treatment. Stage explained 25.4% of the survival variation. In addition to stage, the 19 comorbidities explained 6.1%, treatments 9.2%, age 3.7% and histology 1.3%. Thirteen uncommon comorbidities (prevalence <6%) affected 21.2% of patients and explained 3.5% of the survival variation. Comorbidity count and the Charlson index were significant predictors but explained only 2.5% and 2.0% of the survival variation, respectively. Comorbidity has a major impact on survival in early-and late-stage disease, and even infrequent deleterious comorbidities are important collectively. Comorbidity count and the Charlson index failed to capture much information. Clinical practice and trials need to consider the effect of comorbidity in lung cancer patients. © 2002 Wiley-Liss, Inc. Key words: lung cancer; comorbidity; treatment; survival; prognosisLung cancer is the leading cause of cancer death in men and women in the United States; in the year 2001, there were an estimated 169,500 new cases and 157,400 deaths due to lung cancer. 1 Approximately 8% of men and 6% of women in the United States develop lung cancer, 2 and approximately 90% of lung cancers have been attributed to cigarette smoking. 2,3 The prognosis for lung cancer patients is poor, with crude 5-year survival proportions being approximately 13-15%; survival has improved little over the last 25 years. 2,4 Comorbidity is the occurrence of concomitant disease in addition to an index disease of interest or the simultaneous occurrence of multiple diseases in an individual. Lung cancer is associated with age and smoking, and both age 5,6 and smoking 7,8 are strongly associated with comorbidity. Thus, it is expected that comorbidity has an important impact in lung cancer patients, yet to date comorbidity has not been well studied in this population. In studies of breast, endometrial, prostate, colorectal and head-and-neck cancer patients, comorbidity has had a negative impact on several health ...

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10−13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations.