Clinical Pathology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 103
  • Item
    Thumbnail Image
    Intratumoral presence of the genotoxic gut bacteria pks+ E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer
    Joo, JE ; Chu, YL ; Georgeson, P ; Walker, R ; Mahmood, K ; Clendenning, M ; Meyers, AL ; Como, J ; Joseland, S ; Preston, SG ; Diepenhorst, N ; Toner, J ; Ingle, DJ ; Sherry, NL ; Metz, A ; Lynch, BM ; Milne, RL ; Southey, MC ; Hopper, JL ; Win, AK ; Macrae, FA ; Winship, IM ; Rosty, C ; Jenkins, MA ; Buchanan, DD (Springer Nature, 2024)
    Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+ Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). Conclusion: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.
  • Item
    No Preview Available
    Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
    Fernandez-Rozadilla, C ; Timofeeva, M ; Chen, Z ; Law, P ; Thomas, M ; Bien, S ; Diez-Obrero, V ; Li, L ; Fernandez-Tajes, J ; Palles, C ; Sherwood, K ; Harris, S ; Svinti, V ; McDonnell, K ; Farrington, S ; Studd, J ; Vaughan-Shaw, P ; Shu, X-O ; Long, J ; Cai, Q ; Guo, X ; Lu, Y ; Scacheri, P ; Studd, J ; Huyghe, J ; Harrison, T ; Shibata, D ; Haiman, C ; Devall, M ; Schumacher, F ; Melas, M ; Rennert, G ; Obon-Santacana, M ; Martin-Sanchez, V ; Moratalla-Navarro, F ; 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 ; Potter, J ; Jenkins, M ; Win, AK ; Pai, R ; Figueiredo, J ; Haile, R ; Gallinger, S ; Woods, M ; Newcomb, P ; Shibata, D ; Cheadle, J ; Kaplan, R ; Maughan, T ; Kerr, R ; Kerr, D ; Kirac, I ; Boehm, J ; Mecklin, L-P ; Jousilahti, P ; Knekt, P ; Aaltonen, L ; Rissanen, H ; Pukkala, E ; Eriksson, J ; Cajuso, T ; Hanninen, U ; Kondelin, J ; Palin, K ; Tanskanen, T ; Renkonen-Sinisalo, L ; Zanke, B ; Mannisto, S ; Albanes, D ; Weinstein, S ; Ruiz-Narvaez, E ; Palmer, J ; Buchanan, D ; Platz, E ; Visvanathan, K ; Ulrich, C ; Siegel, E ; Brezina, S ; Gsur, A ; Campbell, P ; Chang-Claude, J ; Hoffmeister, M ; Brenner, H ; Slattery, M ; Potter, J ; Tsilidis, K ; Schulze, M ; Gunter, M ; Murphy, N ; Castells, A ; Castellvi-Bel, S ; Moreira, L ; Arndt, V ; Shcherbina, A ; Stern, M ; Pardamean, B ; Bishop, T ; Giles, G ; Southey, M ; Idos, G ; McDonnell, K ; Abu-Ful, Z ; Greenson, J ; Shulman, K ; Lejbkowicz, F ; Offit, K ; Su, Y-R ; Steinfelder, R ; Keku, T ; van Guelpen, B ; Hudson, T ; Hampel, H ; Pearlman, R ; Berndt, S ; Hayes, R ; Martinez, ME ; Thomas, S ; Corley, D ; Pharoah, P ; Larsson, S ; Yen, Y ; Lenz, H-J ; White, E ; Li, L ; Doheny, K ; Pugh, E ; Shelford, T ; Chan, A ; Cruz-Correa, M ; Lindblom, A ; Shibata, D ; Joshi, A ; Schafmayer, C ; Scacheri, P ; Kundaje, A ; Nickerson, D ; Schoen, R ; Hampe, J ; Stadler, Z ; Vodicka, P ; Vodickova, L ; Vymetalkova, V ; Papadopoulos, N ; Edlund, C ; Gauderman, W ; Thomas, D ; Shibata, D ; Toland, A ; Markowitz, S ; Kim, A ; Gruber, S ; van Duijnhoven, F ; Feskens, E ; Sakoda, L ; Gago-Dominguez, M ; Wolk, A ; Naccarati, A ; Pardini, B ; FitzGerald, L ; Lee, SC ; Ogino, S ; Bien, S ; Kooperberg, C ; Li, C ; Lin, Y ; Prentice, R ; Qu, C ; Bezieau, S ; Tangen, C ; Mardis, E ; Yamaji, T ; Sawada, N ; Iwasaki, M ; Haiman, C ; Le Marchand, L ; Wu, A ; Qu, C ; McNeil, C ; Coetzee, G ; Hayward, C ; Deary, I ; Harris, S ; Theodoratou, E ; Reid, S ; Walker, M ; Ooi, LY ; Moreno, V ; Casey, G ; Gruber, S ; Tomlinson, I ; Zheng, W ; Dunlop, M ; Houlston, R ; Peters, U (NATURE PORTFOLIO, 2023-01)
    Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
  • Item
    No Preview Available
    Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis.
    Lu, Y ; Zhao, YC ; Chang-Claude, J ; Gruber, SB ; Gsur, A ; Offit, K ; Vodickova, L ; Woods, MO ; Nguyen, LH ; Wade, KH ; Carreras-Torres, R ; Moreno, V ; Buchanan, DD ; Cotterchio, M ; Chan, AT ; Phipps, AI ; Peters, U ; Song, M (American Association for Cancer Research (AACR), 2023-02-06)
    BACKGROUND: Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS: We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS: We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS: Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT: Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk.
  • Item
    Thumbnail Image
    DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
    Walker, R ; Mahmood, K ; Como, J ; Clendenning, M ; Joo, JE ; Georgeson, P ; Joseland, S ; Preston, SG ; Pope, BJ ; Chan, JM ; Austin, R ; Bojadzieva, J ; Campbell, A ; Edwards, E ; Gleeson, M ; Goodwin, A ; Harris, MT ; Ip, E ; Kirk, J ; Mansour, J ; Fan, HM ; Nichols, C ; Pachter, N ; Ragunathan, A ; Spigelman, A ; Susman, R ; Christie, M ; Jenkins, MA ; Pai, RK ; Rosty, C ; Macrae, FA ; Winship, IM ; Buchanan, DD (MDPI, 2023-10)
    Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
  • Item
    No Preview Available
    A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
    Aglago, EK ; Kim, A ; Lin, Y ; Qu, C ; Evangelou, M ; Ren, Y ; Morrison, J ; Albanes, D ; Arndt, V ; Barry, EL ; Baurley, JW ; Berndt, S ; Bien, SA ; Bishop, DT ; Bouras, E ; Brenner, H ; Buchanan, DD ; Budiarto, A ; Carreras-Torres, R ; Casey, G ; Cenggoro, TW ; Chen, AT ; Chang-Claude, J ; Chen, X ; Conti, D ; 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 ; Le Marchand, L ; Lewinger, JP ; Li, L ; Lynch, BM ; Mahesworo, B ; Mandic, M ; Obon-Santacana, M ; Morento, V ; Murphy, N ; Men, 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, FJB ; 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, PT (AMER ASSOC CANCER RESEARCH, 2023-08-01)
    UNLABELLED: Colorectal 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
    No Preview Available
    Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
    Yarmolinsky, J ; Robinson, JW ; Mariosa, D ; Karhunen, V ; Huang, J ; Dimou, N ; Murphy, N ; Burrows, K ; Bouras, E ; Smith-Byrne, K ; Lewis, SJ ; Galesloot, TE ; Kiemeney, LA ; Vermeulen, S ; Martin, P ; Albanes, D ; Hou, L ; Newcomb, PA ; White, E ; Wolk, A ; Wu, AH ; Marchand, LL ; Phipps, AI ; Buchanan, DD ; International Lung Cancer Consortium, PRACTICAL consortium, ; Zhao, SS ; Gill, D ; Chanock, SJ ; Purdue, MP ; Smith, GD ; Brennan, P ; Herzig, K-H ; Jarvelin, M-R ; Dehghan, A ; Johansson, M ; Gunter, MJ ; Tsilidis, KK ; Martin, RM (Cold Spring Harbor Laboratory, 2023-05-05)
    BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. RESULTS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. CONCLUSION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
  • Item
    No Preview Available
    Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes
    Mahmood, K ; Thomas, M ; Qu, C ; Hsu, L ; Buchanan, DD ; Peters, U (W B SAUNDERS CO-ELSEVIER INC, 2023-10)
  • Item
    Thumbnail Image
    A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
    Walker, R ; Clendenning, M ; Joo, JE ; Xue, J ; Mahmood, K ; Georgeson, P ; Como, J ; Joseland, S ; Preston, SG ; Chan, JM ; Jenkins, MA ; Rosty, C ; Macrae, FA ; Di Palma, S ; Campbell, A ; Winship, IM ; Buchanan, DD (SPRINGER, 2023-10)
    Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.
  • Item
    No Preview Available
    Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases
    Ugai, T ; Akimoto, N ; Haruki, K ; Harrison, TA ; Cao, Y ; Qu, C ; Chan, AT ; Campbell, PT ; Berndt, S ; Buchanan, DD ; Cross, AJ ; Diergaarde, B ; Gallinger, SJ ; Gunter, MJ ; Harlid, S ; Hidaka, A ; Hoffmeister, M ; Brenner, H ; Chang-Claude, J ; Hsu, L ; Jenkins, MA ; Lin, Y ; Milne, RL ; Moreno, V ; Newcomb, PA ; Nishihara, R ; Obon-Santacana, M ; Pai, RK ; Sakoda, LC ; Schoen, RE ; Slattery, ML ; Sun, W ; Amitay, EL ; Alwers, E ; Thibodeau, SN ; Toland, AE ; Van Guelpen, B ; Zaidi, SH ; Potter, JD ; Meyerhardt, JA ; Giannakis, M ; Song, M ; Nowak, JA ; Peters, U ; Phipps, A ; Ogino, S (SPRINGER JAPAN KK, 2023-03)
    BACKGROUND: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. METHODS: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. RESULTS: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70-0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15-3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. CONCLUSIONS: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
  • Item
    No Preview Available
    Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.
    Su, Y-R ; Sakoda, LC ; Jeon, J ; Thomas, M ; Lin, Y ; Schneider, JL ; Udaltsova, N ; Lee, JK ; Lansdorp-Vogelaar, I ; Peterse, EFP ; Zauber, AG ; Zheng, J ; Zheng, Y ; Hauser, E ; Baron, JA ; Barry, EL ; Bishop, DT ; Brenner, H ; Buchanan, DD ; Burnett-Hartman, A ; Campbell, PT ; Casey, G ; Castellví-Bel, S ; Chan, AT ; Chang-Claude, J ; Figueiredo, JC ; Gallinger, SJ ; Giles, GG ; Gruber, SB ; Gsur, A ; Gunter, MJ ; Hampe, J ; Hampel, H ; Harrison, TA ; Hoffmeister, M ; Hua, X ; Huyghe, JR ; Jenkins, MA ; Keku, TO ; Marchand, LL ; Li, L ; Lindblom, A ; Moreno, V ; Newcomb, PA ; Pharoah, PDP ; Platz, EA ; Potter, JD ; Qu, C ; Rennert, G ; Schoen, RE ; Slattery, ML ; Song, M ; van Duijnhoven, FJB ; Van Guelpen, B ; Vodicka, P ; Wolk, A ; Woods, MO ; Wu, AH ; Hayes, RB ; Peters, U ; Corley, DA ; Hsu, L (American Association for Cancer Research (AACR), 2023-03-06)
    BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.