Biology subjects

Pharoah, P. D.

Publications and source records attributed to Pharoah, P. D..

2 recordsLinked to original sources

bioRxiv2020

Transcriptome and interactome analyses identify the TP53 interacting gene RCCD1 as a candidate susceptibility gene at the 15p26.1 breast and ovarian cancer risk locus

Common genetic variation in a region on chromosome 15q26 confers susceptibility to breast and ovarian cancer. The P53 interacting gene RCCD1 in this region is a candidate susceptibility gene for both cancers. In this study, a colocalization analysis of breast and ovarian cancer case-control genetic association studies in over 145,000 and 146,000 controls fine mapped the shared association in this region to 17 pleiotropic credible causal risk variants (Pbreast < 1.16 x 10-14 and P ovary < 7.50 x 10-7). These variants were strongly associated with the expression of RCCD1 in normal breast and ovarian tissues. Circular chromosome conformation capture (4C) analysis of RCCD1 in breast and ovarian cancer cells identified similar patterns of cis-interaction and significant binding site enrichment for the BRCA2 interacting gene EMSY (Padjusted = 9.24 x 10-6). The 4C analysis pinpointed a single 2kB RCCD1 cis-interaction that contained two of the 17 shared risk variants. RCCD1 trans-interacting regions mapped to previously identified genome wide significant (P < 5 x 10-8) breast cancer risk loci (1p34.2 and 3p14.1) and to the pleiotropic breast-ovarian cancer risk locus at chromosome 9q34.2. Stable overexpression of RCCD1 in breast and ovarian cancer precursor cells identified 13 and 11 differentially expressed genes (DEGs) respectively associated with breast and ovarian cancer risk at genome-wide significance (PMAGMA < 2.6 x 10-6 after Bonferroni correction). Eighty-two DEGs shared between breast and ovarian cancer were strongly enriched in TP53 (P = 9.9 x 10-4), Hippo (P = 2.51 x 10-3) and TNF signaling (P = 4.7 x 10-3) pathways.

genetics↗

bioRxiv2019

Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis

ObjectivesTo determine whether cancer confers protection against Alzheimers disease and to evaluate the relationship in the context of smoking-related cancers versus non-smoking related cancers\n\nDesignMendelian randomization analysis using cancer-associated genetic variants as instrumental variables\n\nSettingInternational Genomics of Alzheimers Project\n\nParticipants17,008 Alzheimers disease cases and 37,154 controls\n\nMain outcome measuresOdds ratio of Alzheimers disease per 1-unit higher log odds of genetically predicted cancer\n\nResultsWe found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84-0.99, p=0.019), leukemia (OR 0.98, 95% CI 0.96-0.995, p=0.012), and breast cancer (OR 0.94, 95% CI 0.89-0.99, p=0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of Alzheimers disease, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of Alzheimers disease (OR 0.98, 95% CI 0.96-0.988, p=0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with Alzheimers disease than non-smoking related cancers (5.2% lower odds, OR 0.95, 95% CI 0.92-0.98, p=0.0026, vs. 1.9% lower odds, OR 0.98, 95% CI 0.97-0.995, p=0.0091).\n\nConclusionsGenetically predicted lung cancer, leukemia, breast cancer, and all cancers in aggregate are associated with lower odds of incident Alzheimers disease. Furthermore, the risk of Alzheimers disease was lower in smoking-related versus non-smoking related cancers. These results add to the substantial epidemiological evidence of an inverse association between history of cancer and lower odds of Alzheimers disease, by suggesting a causal basis for this relationship.

epidemiology↗