A systematic SNP selection approach to identify mechanisms underlying disease aetiology: Linking height to post-menopausal breast and colorectal cancer risk

Data from GWAS suggest that SNPs associated with complex diseases or traits tend to co-segregate in regions of low recombination, harbouring functionally linked gene clusters. This phenomenon allows for selecting a limited number of SNPs from GWAS repositories for large-scale studies investigating shared mechanisms between diseases. For example, we were interested in shared mechanisms between adult-attained height and post-menopausal breast cancer (BC) and colorectal cancer (CRC) risk, because height is a risk factor for these cancers, though likely not a causal factor. Using SNPs from public GWAS repositories at p-values < 1 × 10-5 and a genomic sliding window of 1 mega base pair, we identified SNP clusters including at least one SNP associated with height and one SNP associated with either post-menopausal BC or CRC risk (or both). SNPs were annotated to genes using HapMap and GRAIL and analysed for significantly overrepresented pathways using ConsensuspathDB. Twelve clusters including 56 SNPs annotated to 26 genes were prioritised because these included at least one height- and one BC risk- or CRC risk-associated SNP annotated to the same gene. Annotated genes were involved in Indian hedgehog signalling (p-value = 7.78 × 10-7) and several cancer site-specific pathways. This systematic approach identified a limited number of clustered SNPs, which pinpoint potential shared mechanisms linking together the complex phenotypes height, post-menopausal BC and CRC

Dietary folate and folate vitamers and the risk of prostate cancer in The Netherlands Cohort Study

Purpose: The aim of the present study was to examine the association between intake of folate, and specific folate vitamers, and the risk of advanced and total prostate cancer. Methods: The association between dietary folate and prostate cancer risk was evaluated in The Netherlands Cohort Study (NLCS) on diet and cancer, conducted among 58,279 men ages 55-69 years at baseline. Information on diet was collected at baseline by means of food frequency questionnaires. Incident cases were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. After 17.3 years of follow-up, 3,669 incident prostate cancer cases, of which 1,290 advanced cases, and 2,336 male subcohort members were available for case-cohort analyses. Results: Dietary folate was not associated with prostate cancer risk, nor with the risk of advanced prostate cancer, among men in the NLCS cohort (HR = 1.05, 95 % CI: 0.87-1.26 and HR = 1.09, 95 % CI: 0.88-1.35, respectively, for the highest quintile of folate intake vs. the lowest quintile). Specific folate vitamers were neither associated with the risk of prostate cancer or risk of advanced prostate cancer. Conclusions: Our results do not support an association of dietary folate or specific folate vitamers on the risk of prostate cancer, or advanced prostate cancer. © 2012 Springer Science+Business Media Dordrecht

Autosomal dominant inheritance of prostate cancer: A confirmatory study

Objectives. To confirm, in a study of a large, independent cohort of families with prostate cancer, the findings of three segregation analyses that have suggested the existence of an inherited form of prostate cancer with an autosomal dominant inheritance mode. Methods. Between January 1991 and December 1993, 1199 pedigrees were ascertained through single, unrelated, prostate cancer probands who presented for radical prostatectomy at the Division of Urologic Surgery, Washington University Medical Center in St. Louis, Missouri. Maximum likelihood segregation analysis was used to test specifically for mendelian inheritance of prostate cancer. Results. Segregation analyses revealed that the familial aggregation of prostate cancer can be best explained by the autosomal dominant inheritance of a rare (q = 0.0037) high-risk allele. According to the best-fitting autosomal dominant model, 97% of all carriers will be affected by 85 years of age compared with 10% of noncarriers. Furthermore, the autosomal dominant model predicts that the high-risk allele accounts for a large proportion (65%) of all patients diagnosed with prostate cancer before 56 years of age. However, of all prostate cancer cases, a relatively small proportion is inherited (8% by 85 years old). Conclusions. These results are in agreement with earlier reports of segregation analyses of prostate cancer and strengthen the evidence that prostate cancer is inherited in a mendelian fashion within a subset of families. Copyright © 2001 Elsevier Science Inc

A Systematic Literature Review and Meta-Regression Analysis on Early-Life Energy Restriction and Cancer Risk in Humans

<div><p>Background</p><p>In animal models, long-term moderate energy restriction (ER) is reported to decelerate carcinogenesis, whereas the effect of severe ER is inconsistent. The impact of early-life ER on cancer risk has never been reviewed systematically and quantitatively based on observational studies in humans.</p><p>Objective</p><p>We conducted a systematic review of observational studies and a meta-(regression) analysis on cohort studies to clarify the association between early-life ER and organ site-specific cancer risk.</p><p>Methods</p><p>PubMed and EMBASE (1982 –August 2015) were searched for observational studies. Summary relative risks (RRs) were estimated using a random effects model when available ≥3 studies.</p><p>Results</p><p>Twenty-four studies were included. Eleven publications, emanating from seven prospective cohort studies and some reporting on multiple cancer endpoints, met the inclusion criteria for quantitative analysis. Women exposed to early-life ER (ranging from 220–1660 kcal/day) had a higher breast cancer risk than those not exposed (RR_{RE all ages} = 1.28, 95% CI: 1.05–1.56; RR_{RE for 10–20 years of age} = 1.21, 95% CI: 1.09–1.34). Men exposed to early-life ER (ranging from 220–800kcal/day) had a higher prostate cancer risk than those not exposed (RR_RE = 1.16, 95% CI: 1.03–1.30). Summary relative risks were not computed for colorectal cancer, because of heterogeneity, and for stomach-, pancreas-, ovarian-, and respiratory cancer because there were <3 available studies. Longer duration of exposure to ER, after adjustment for severity, was positively associated with overall cancer risk in women (<i>p</i> = 0.02). Ecological studies suggest that less severe ER is generally associated with a reduced risk of cancer.</p><p>Conclusions</p><p>Early-life transient severe ER seems to be associated with increased cancer risk in the breast (particularly ER exposure at adolescent age) and prostate. The duration, rather than severity of exposure to ER, seems to positively influence relative risk estimates. This result should be interpreted with caution due to the limited number of studies and difficulty in disentangling duration, severity, and geographical setting of exposure.</p></div