Clinical Pathology - Research Publications

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Author: Buchanan, Daniel × Author: Giles, Graham × Author: Joo, Ji Hoon × End date: 2022 × Start date: 2022 × Type: Journal Article ×

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    Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?
    Yu, C ; Hodge, AM ; Wong, EM ; Joo, JE ; Makalic, E ; Schmidt, DF ; Buchanan, DD ; Severi, G ; Hopper, JL ; English, DR ; Giles, GG ; Milne, RL ; Southey, MC ; Dugue, P-A (TAYLOR & FRANCIS INC, 2022-12-02)
    Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10-14), ~0.6% (P = 2 × 10-7), and ~8.7% (P = 7 × 10-87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P < 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAge and GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoking (interaction term: -0.022, standard error [SE] = 0.012, P = 0.058) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.030, SE = 0.015, P = 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.
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    Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures
    Georgeson, P ; Harrison, TA ; Pope, BJ ; Zaidi, SH ; Qu, C ; Steinfelder, RS ; Lin, Y ; Joo, JE ; Mahmood, K ; Clendenning, M ; Walker, R ; Amitay, EL ; Berndt, S ; Brenner, H ; Campbell, PT ; Cao, Y ; Chan, AT ; Chang-Claude, J ; Doheny, KF ; Drew, DA ; Figueiredo, JC ; French, AJ ; Gallinger, S ; Giannakis, M ; Giles, GG ; Gsur, A ; Gunter, MJ ; Hoffmeister, M ; Hsu, L ; Huang, W-Y ; Limburg, P ; Manson, JE ; Moreno, V ; Nassir, R ; Nowak, JA ; Obon-Santacana, M ; Ogino, S ; Phipps, A ; Potter, JD ; Schoen, RE ; Sun, W ; Toland, AE ; Trinh, QM ; Ugai, T ; Macrae, FA ; Rosty, C ; Hudson, TJ ; Jenkins, MA ; Thibodeau, SN ; Winship, IM ; Peters, U ; Buchanan, DD (NATURE PORTFOLIO, 2022-06-06)
    Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.