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Item Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.(Springer Nature, 2023-10-02) Thomas M; Su Y-R; Rosenthal EA; Sakoda LC; Schmit SL; Timofeeva MN; Chen Z; Fernandez-Rozadilla C; Law PJ; Murphy N; Carreras-Torres R; Diez-Obrero V; van Duijnhoven FJB; Jiang S; Shin A; Wolk A; Phipps AI; Burnett-Hartman A; Gsur A; Chan AT; Zauber AG; Wu AH; Lindblom A; Um CY; Tangen CM; Gignoux C; Newton C; Haiman CA; Qu C; Bishop DT; Buchanan DD; Crosslin DR; Conti DV; Kim D-H; Hauser E; White E; Siegel E; Schumacher FR; Rennert G; Giles GG; Hampel H; Brenner H; Oze I; Oh JH; Lee JK; Schneider JL; Chang-Claude J; Kim J; Huyghe JR; Zheng J; Hampe J; Greenson J; Hopper JL; Palmer JR; Visvanathan K; Matsuo K; Matsuda K; Jung KJ; Li L; Le Marchand L; Vodickova L; Bujanda L; Gunter MJ; Matejcic M; Jenkins MA; Slattery ML; D'Amato M; Wang M; Hoffmeister M; Woods MO; Kim M; Song M; Iwasaki M; Du M; Udaltsova N; Sawada N; Vodicka P; Campbell PT; Newcomb PA; Cai Q; Pearlman R; Pai RK; Schoen RE; Steinfelder RS; Haile RW; Vandenputtelaar R; Prentice RL; Küry S; Castellví-Bel S; Tsugane S; Berndt SI; Lee SC; Brezina S; Weinstein SJ; Chanock SJ; Jee SH; Kweon S-S; Vadaparampil S; Harrison TA; Yamaji T; Keku TO; Vymetalkova V; Arndt V; Jia W-H; Shu X-O; Lin Y; Ahn Y-O; Stadler ZK; Van Guelpen B; Ulrich CM; Platz EA; Potter JD; Li CI; Meester R; Moreno V; Figueiredo JC; Casey G; Lansdorp Vogelaar I; Dunlop MG; Gruber SB; Hayes RB; Pharoah PDP; Houlston RS; Jarvik GP; Tomlinson IP; Zheng W; Corley DA; Peters U; Hsu LPolygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.Item Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.(Springer Nature, 2023-06-26) Dimou N; Kim AE; Flanagan O; Murphy N; Diez-Obrero V; Shcherbina A; Aglago EK; Bouras E; Campbell PT; Casey G; Gallinger S; Gruber SB; Jenkins MA; Lin Y; Moreno V; Ruiz-Narvaez E; Stern MC; Tian Y; Tsilidis KK; Arndt V; Barry EL; Baurley JW; Berndt SI; Bézieau S; Bien SA; Bishop DT; Brenner H; Budiarto A; Carreras-Torres R; Cenggoro TW; Chan AT; Chang-Claude J; Chanock SJ; Chen X; Conti DV; Dampier CH; Devall M; Drew DA; Figueiredo JC; Giles GG; Gsur A; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jordahl K; Kawaguchi E; Keku TO; Larsson SC; Le Marchand L; Lewinger JP; Li L; Mahesworo B; Morrison J; Newcomb PA; Newton CC; Obon-Santacana M; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Peoples AR; Pharoah PDP; Platz EA; Potter JD; Rennert G; Scacheri PC; Schoen RE; Su Y-R; Tangen CM; Thibodeau SN; Thomas DC; Ulrich CM; Um CY; van Duijnhoven FJB; Visvanathan K; Vodicka P; Vodickova L; White E; Wolk A; Woods MO; Qu C; Kundaje A; Hsu L; Gauderman WJ; Gunter MJ; Peters UBACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.Item Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.(American Association for the Advancement of Science, 2024-05-29) Drew DA; Kim AE; Lin Y; Qu C; Morrison J; Lewinger JP; Kawaguchi E; Wang J; Fu Y; Zemlianskaia N; Díez-Obrero V; Bien SA; Dimou N; Albanes D; Baurley JW; Wu AH; Buchanan DD; Potter JD; Prentice RL; Harlid S; Arndt V; Barry EL; Berndt SI; Bouras E; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Chang-Claude J; Conti DV; Devall MAM; Figueiredo JC; Gruber SB; Gsur A; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl KM; Kundaje A; Le Marchand L; Li L; Lynch BM; Murphy N; Nassir R; Newcomb PA; Newton CC; Obón-Santacana M; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Stern MC; Su Y-R; Thomas DC; Tian Y; Tsilidis KK; Ulrich CM; Um CY; van Duijnhoven FJB; Van Guelpen B; White E; Hsu L; Moreno V; Peters U; Chan AT; Gauderman WJRegular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.Item A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.(American Association for Cancer Research, 2023-08-01) Aglago EK; Kim A; Lin Y; Qu C; Evangelou M; Ren Y; Morrison J; Albanes D; Arndt V; Barry EL; Baurley JW; Berndt SI; Bien SA; Bishop DT; Bouras E; Brenner H; Buchanan DD; Budiarto A; Carreras-Torres R; Casey G; Cenggoro TW; Chan AT; Chang-Claude J; Chen X; Conti DV; Devall M; Diez-Obrero V; Dimou N; Drew D; Figueiredo JC; Gallinger S; Giles GG; Gruber SB; Gsur A; Gunter MJ; Hampel H; Harlid S; Hidaka A; Harrison TA; Hoffmeister M; Huyghe JR; Jenkins MA; Jordahl K; Joshi AD; Kawaguchi ES; Keku TO; Kundaje A; Larsson SC; Marchand LL; Lewinger JP; Li L; Lynch BM; Mahesworo B; Mandic M; Obón-Santacana M; Moreno V; Murphy N; Nan H; Nassir R; Newcomb PA; Ogino S; Ose J; Pai RK; Palmer JR; Papadimitriou N; Pardamean B; Peoples AR; Platz EA; Potter JD; Prentice RL; Rennert G; Ruiz-Narvaez E; Sakoda LC; Scacheri PC; Schmit SL; Schoen RE; Shcherbina A; Slattery ML; Stern MC; Su Y-R; Tangen CM; Thibodeau SN; Thomas DC; Tian Y; Ulrich CM; van Duijnhoven FJ; Van Guelpen B; Visvanathan K; Vodicka P; Wang J; White E; Wolk A; Woods MO; Wu AH; Zemlianskaia N; Hsu L; Gauderman WJ; Peters U; Tsilidis KK; Campbell PTColorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.Item A perspective on green, blue, and grey spaces, biodiversity, microbiota, and human health.(Elsevier B.V., 2023-09-20) Potter JD; Brooks C; Donovan G; Cunningham C; Douwes JHumans have lived from equator to poles for millennia but are now increasingly intruding into the wild spaces of other species and steadily extruding ourselves from our own wild spaces, with a profound impact on: our relationship with the natural world; survival of other species; pollution; climate change; etc. We have yet to grasp how these changes directly impact our own health. The primary focus of this paper is on the beneficial influence of proximity to the natural environment. We summarize the evidence for associations between exposure to green space and blue space and improvements in health. In contrast, grey space - the urban landscape - largely presents hazards as well as reducing exposure to green and blue space and isolating us from the natural environment. We discuss various hypotheses that might explain why green, blue, and grey space affect health and focus particularly on the importance of the biodiversity hypothesis and the role of microbiota. We discuss possible mechanisms and exposure routes - air, soil, and water. We highlight the problem of exposure assessment, noting that many of our current tools are not fit for the purpose of understanding exposure to green and blue space, aerosols, soils, and water. We briefly discuss possible differences between indigenous perspectives on the nature of our relationship with the environment and the more dominant international-science view. Finally, we present research gaps and discuss future directions, particularly focusing on the ways in which we might - even in the absence of a full understanding of the mechanisms by which blue, green, and grey space affect our health - begin to implement policies to restore some balance to our environment of with the aim of reducing the large global burden of ill health.Item Genome-wide interaction analysis of folate for colorectal cancer risk.(Elsevier B.V., 2023-11) Bouras E; Kim AE; Lin Y; Morrison J; Du M; Albanes D; Barry EL; Baurley JW; Berndt SI; Bien SA; Bishop TD; Brenner H; Budiarto A; Burnett-Hartman A; Campbell PT; Carreras-Torres R; Casey G; Cenggoro TW; Chan AT; Chang-Claude J; Conti DV; Cotterchio M; Devall M; Diez-Obrero V; Dimou N; Drew DA; Figueiredo JC; Giles GG; Gruber SB; Gunter MJ; Harrison TA; Hidaka A; Hoffmeister M; Huyghe JR; Joshi AD; Kawaguchi ES; Keku TO; Kundaje A; Le Marchand L; Lewinger JP; Li L; Lynch BM; Mahesworo B; Männistö S; Moreno V; Murphy N; Newcomb PA; Obón-Santacana M; Ose J; Palmer JR; Papadimitriou N; Pardamean B; Pellatt AJ; Peoples AR; Platz EA; Potter JD; Qi L; Qu C; Rennert G; Ruiz-Narvaez E; Sakoda LC; Schmit SL; Shcherbina A; Stern MC; Su Y-R; Tangen CM; Thomas DC; Tian Y; Um CY; van Duijnhoven FJ; Van Guelpen B; Visvanathan K; Wang J; White E; Wolk A; Woods MO; Ulrich CM; Hsu L; Gauderman WJ; Peters U; Tsilidis KKBackground Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC. Objectives Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. Methods We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). Results Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. Conclusions Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.Item Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer.(BioMed Central, 2023-10-13) Nimptsch K; Aleksandrova K; Pham TT; Papadimitriou N; Janke J; Christakoudi S; Heath A; Olsen A; Tjønneland A; Schulze MB; Katzke V; Kaaks R; van Guelpen B; Harbs J; Palli D; Macciotta A; Pasanisi F; Yohar SMC; Guevara M; Amiano P; Grioni S; Jakszyn PG; Figueiredo JC; Samadder NJ; Li CI; Moreno V; Potter JD; Schoen RE; Um CY; Weiderpass E; Jenab M; Gunter MJ; Pischon TBACKGROUND: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. METHODS: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. RESULTS: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). CONCLUSIONS: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.Item Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.(Springer Nature, 2024-04-26) Chen Z; Guo X; Tao R; Huyghe JR; Law PJ; Fernandez-Rozadilla C; Ping J; Jia G; Long J; Li C; Shen Q; Xie Y; Timofeeva MN; Thomas M; Schmit SL; Díez-Obrero V; Devall M; Moratalla-Navarro F; Fernandez-Tajes J; Palles C; Sherwood K; Briggs SEW; Svinti V; Donnelly K; Farrington SM; Blackmur J; Vaughan-Shaw PG; Shu X-O; Lu Y; Broderick P; Studd J; Harrison TA; Conti DV; Schumacher FR; Melas M; Rennert G; Obón-Santacana M; Martín-Sánchez V; Oh JH; Kim J; Jee SH; Jung KJ; Kweon S-S; Shin M-H; Shin A; Ahn Y-O; Kim D-H; Oze I; Wen W; Matsuo K; Matsuda K; Tanikawa C; Ren Z; Gao Y-T; Jia W-H; Hopper JL; Jenkins MA; Win AK; Pai RK; Figueiredo JC; Haile RW; Gallinger S; Woods MO; Newcomb PA; Duggan D; Cheadle JP; Kaplan R; Kerr R; Kerr D; Kirac I; Böhm J; Mecklin J-P; Jousilahti P; Knekt P; Aaltonen LA; Rissanen H; Pukkala E; Eriksson JG; Cajuso T; Hänninen U; Kondelin J; Palin K; Tanskanen T; Renkonen-Sinisalo L; Männistö S; Albanes D; Weinstein SJ; Ruiz-Narvaez E; Palmer JR; Buchanan DD; Platz EA; Visvanathan K; Ulrich CM; Siegel E; Brezina S; Gsur A; Campbell PT; Chang-Claude J; Hoffmeister M; Brenner H; Slattery ML; Potter JD; Tsilidis KK; Schulze MB; Gunter MJ; Murphy N; Castells A; Castellví-Bel S; Moreira L; Arndt V; Shcherbina A; Bishop DT; Giles GG; Southey MC; Idos GE; McDonnell KJ; Abu-Ful Z; Greenson JK; Shulman K; Lejbkowicz F; Offit K; Su Y-R; Steinfelder R; Keku TO; van Guelpen B; Hudson TJ; Hampel H; Pearlman R; Berndt SI; Hayes RB; Martinez ME; Thomas SS; Pharoah PDP; Larsson SC; Yen Y; Lenz H-J; White E; Li L; Doheny KF; Pugh E; Shelford T; Chan AT; Cruz-Correa M; Lindblom A; Hunter DJ; Joshi AD; Schafmayer C; Scacheri PC; Kundaje A; Schoen RE; Hampe J; Stadler ZK; Vodicka P; Vodickova L; Vymetalkova V; Edlund CK; Gauderman WJ; Shibata D; Toland A; Markowitz S; Kim A; Chanock SJ; van Duijnhoven F; Feskens EJM; Sakoda LC; Gago-Dominguez M; Wolk A; Pardini B; FitzGerald LM; Lee SC; Ogino S; Bien SA; Kooperberg C; Li CI; Lin Y; Prentice R; Qu C; Bézieau S; Yamaji T; Sawada N; Iwasaki M; Le Marchand L; Wu AH; Qu C; McNeil CE; Coetzee G; Hayward C; Deary IJ; Harris SE; Theodoratou E; Reid S; Walker M; Ooi LY; Lau KS; Zhao H; Hsu L; Cai Q; Dunlop MG; Gruber SB; Houlston RS; Moreno V; Casey G; Peters U; Tomlinson I; Zheng WGenome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.Item Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures(Springer Nature Limited, 6/06/2022) 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 SI; 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; Obón-Santacana M; Ogino S; Phipps AI; 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 DDCarriers 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.Item Human papillomavirus self-testing among unscreened and under-screened Māori, Pasifika and Asian women in Aotearoa New Zealand: A preference survey among responders and interviews with clinical-trial nonresponders(John Wiley and Sons Ltd, 2022-12) Sherman SM; Brewer N; Bartholomew K; Bromhead C; Crengle S; Cunningham C; Douwes J; Foliaki S; Grant J; Maxwell A; McPherson G; Scott N; Wihongi H; Potter JDINTRODUCTION: Māori, Pasifika and Asian women are less likely to attend cervical screening and Māori and Pasifika women are more likely to be diagnosed with later-stage cervical cancer than other women in Aotearoa New Zealand. This study-with under-screened women taking part in a randomized-controlled trial comparing self-testing and standard screening-explored the acceptability of a human papillomavirus (HPV) self-test kit and the preferred method for receiving it. METHODS: Māori, Pasifika and Asian women (N= 376) completed a cross-sectional postal questionnaire. Twenty-six women who had not accepted the trial invitation were interviewed to understand their reasons for nonparticipation. RESULTS: Most women found the self-test kit easy and convenient to use and reported that they did not find it painful, uncomfortable or embarrassing. This was reflected in the preference for a self-test over a future smear test on the same grounds. Most women preferred to receive the kit by mail and take the test themselves, rather than having it done by a doctor or nurse. There was a range of preferences relating to how to return the kit. Phone calls with nonresponders revealed that, although most had received the test kit, the reasons for not choosing to be involved included not wanting to, being too busy or forgetting. CONCLUSION: HPV self-testing was acceptable for Māori, Pasifika and Asian women in Aotearoa New Zealand. HPV self-testing has considerable potential to reduce the inequities in the current screening programme and should be made available with appropriate delivery options as soon as possible. PATIENT OR PUBLIC CONTRIBUTION: This study explored the acceptability of HPV self-testing and their preferences for engaging with it among Māori, Pasifika and Asian women. Thus, women from these underserved communities were the participants and focus of this study.