Medicine (RMH) - Research Publications

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    Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study
    Anthony, E ; Reece, JC ; Milanzi, E ; Joo, JE ; Joseland, S ; Clendenning, M ; Whelan, A ; Parry, S ; Arnold, J ; Vijay, V ; Atkinson, N ; Hopper, JL ; Win, AK ; Jenkins, MA ; Macrae, FA ; Winship, IM ; Rosty, C ; Buchanan, DD (BMC, 2022-11-26)
    OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.
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    The SCRIPT trial: study protocol for a randomised controlled trial of a polygenic risk score to tailor colorectal cancer screening in primary care
    Saya, S ; Boyd, L ; Chondros, P ; McNamara, M ; King, M ; Milton, S ; Lourenco, RDA ; Clark, M ; Fishman, G ; Marker, J ; Ostroff, C ; Allman, R ; Walter, FM ; Buchanan, D ; Winship, I ; McIntosh, J ; Macrae, F ; Jenkins, M ; Emery, J (BMC, 2022-09-27)
    BACKGROUND: Polygenic risk scores (PRSs) can predict the risk of colorectal cancer (CRC) and target screening more precisely than current guidelines using age and family history alone. Primary care, as a far-reaching point of healthcare and routine provider of cancer screening and risk information, may be an ideal location for their widespread implementation. METHODS: This trial aims to determine whether the SCRIPT intervention results in more risk-appropriate CRC screening after 12 months in individuals attending general practice, compared with standard cancer risk reduction information. The SCRIPT intervention consists of a CRC PRS, tailored risk-specific screening recommendations and a risk report for participants and their GP, delivered in general practice. Patients aged between 45 and 70 inclusive, attending their GP, will be approached for participation. For those over 50, only those overdue for CRC screening will be eligible to participate. Two hundred and seventy-four participants will be randomised to the intervention or control arms, stratified by general practice, using a computer-generated allocation sequence. The primary outcome is risk-appropriate CRC screening after 12 months. For those in the intervention arm, risk-appropriate screening is defined using PRS-derived risk; for those in the control arm, it is defined using family history and national screening guidelines. Timing, type and results of the previous screening are considered in both arms. Objective health service data will capture screening behaviour. Secondary outcomes include cancer-specific worry, risk perception, predictors of CRC screening behaviour, screening intentions and health service use at 1, 6 and 12 months post-intervention delivery. DISCUSSION: This trial aims to determine whether a PRS-derived personalised CRC risk estimate delivered in primary care increases risk-appropriate CRC screening. A future population risk-stratified CRC screening programme could incorporate risk assessment within primary care while encouraging adherence to targeted screening recommendations. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12621000092897p. Registered on 1 February 2021.
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    Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
    Moller, P ; Seppala, T ; Dowty, JG ; Haupt, S ; Dominguez-Valentin, M ; Sunde, L ; Bernstein, I ; Engel, C ; Aretz, S ; Nielsen, M ; Capella, G ; Evans, DG ; Burn, J ; Holinski-Feder, E ; Bertario, L ; Bonanni, B ; Lindblom, A ; Levi, Z ; Macrae, F ; Winship, I ; Plazzer, J-P ; Sijmons, R ; Laghi, L ; Della Valle, A ; Heinimann, K ; Half, E ; Lopez-Koestner, F ; Alvarez-Valenzuela, K ; Scott, RJ ; Katz, L ; Laish, I ; Vainer, E ; Vaccaro, CA ; Carraro, DM ; Gluck, N ; Abu-Freha, N ; Stakelum, A ; Kennelly, R ; Winter, D ; Rossi, BM ; Greenblatt, M ; Bohorquez, M ; Sheth, H ; Tibiletti, MG ; Lino-Silva, LS ; Horisberger, K ; Portenkirchner, C ; Nascimento, I ; Rossi, NT ; da Silva, LA ; Thomas, H ; Zarand, A ; Mecklin, J-P ; Pylvanainen, K ; Renkonen-Sinisalo, L ; Lepisto, A ; Peltomaki, P ; Therkildsen, C ; Lindberg, LJ ; Thorlacius-Ussing, O ; von Knebel Doeberitz, M ; Loeffler, M ; Rahner, N ; Steinke-Lange, V ; Schmiegel, W ; Vangala, D ; Perne, C ; Hueneburg, R ; de Vargas, AF ; Latchford, A ; Gerdes, A-M ; Backman, A-S ; Guillen-Ponce, C ; Snyder, C ; Lautrup, CK ; Amor, D ; Palmero, E ; Stoffel, E ; Duijkers, F ; Hall, MJ ; Hampel, H ; Williams, H ; Okkels, H ; Lubinski, J ; Reece, J ; Ngeow, J ; Guillem, JG ; Arnold, J ; Wadt, K ; Monahan, K ; Senter, L ; Rasmussen, LJ ; van Hest, LP ; Ricciardiello, L ; Kohonen-Corish, MRJ ; Ligtenberg, MJL ; Southey, M ; Aronson, M ; Zahary, MN ; Samadder, NJ ; Poplawski, N ; Hoogerbrugge, N ; Morrison, PJ ; James, P ; Lee, G ; Chen-Shtoyerman, R ; Ankathil, R ; Pai, R ; Ward, R ; Parry, S ; Debniak, T ; John, T ; van Overeem Hansen, T ; Caldes, T ; Yamaguchi, T ; Barca-Tierno, V ; Garre, P ; Cavestro, GM ; Weitz, J ; Redler, S ; Buettner, R ; Heuveline, V ; Hopper, JL ; Win, AK ; Lindor, N ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Figueiredo, J ; Buchanan, DD ; Thibodeau, SN ; ten Broeke, SW ; Hovig, E ; Nakken, S ; Pineda, M ; Duenas, N ; Brunet, J ; Green, K ; Lalloo, F ; Newton, K ; Crosbie, EJ ; Mints, M ; Tjandra, D ; Neffa, F ; Esperon, P ; Kariv, R ; Rosner, G ; Pavicic, WH ; Kalfayan, P ; Torrezan, GT ; Bassaneze, T ; Martin, C ; Moslein, G ; Ahadova, A ; Kloor, M ; Sampson, JR ; Jenkins, MA (BMC, 2022-10-01)
    OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
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    Heterogeneity in the psychosocial and behavioral responses associated with a diagnosis of suspected Lynch syndrome in women with endometrial cancer
    Jonnagadla, S ; Joseland, SL ; Saya, S ; den Elzen, N ; Isbister, J ; Winship, IM ; Buchanan, DD (BMC, 2022-07-15)
    BACKGROUND: A suspected Lynch syndrome (SLS) diagnosis is made when a tumor exhibits DNA mismatch repair deficiency but cannot be definitively assigned to an inherited or non-inherited etiology. This diagnosis poses challenges for healthcare professionals, patients, and their families in managing future cancer risks and clinical care. METHODS: This qualitative study aimed to explore the psychosocial and behavioral responses of endometrial cancer (EC) patients receiving a SLS diagnosis (EC-SLS). Semi-structured telephone interviews were conducted with 15 EC-SLS women, transcribed, and thematically analyzed. RESULTS: Most who interpreted their result as negative for Lynch syndrome (LS) believed they were at population-level risk of cancer and felt happy and relieved. Many participants who interpreted their result as inconclusive/not definitive for LS were confused about their cancer risk and experienced negative emotions of anger and frustration. Despite variation in colorectal cancer screening recommendations reported by participants, most adhered to the advice given. Almost all participants communicated their genetic test result to immediate family members; however, communication of family cancer risk management advice was more limited due to most participants reporting not receiving family screening advice. A family history of cancer and a professional healthcare background influenced participants' engagement in regular cancer screening. CONCLUSION: These findings highlight variability in the psychosocial and behavioral responses associated with EC-SLS, providing insight into how healthcare professionals can optimally manage and support such individuals.
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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.
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    Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
    Palles, C ; West, HD ; Chew, E ; Galavotti, S ; Flensburg, C ; Grolleman, JE ; Jansen, EAM ; Curley, H ; Chegwidden, L ; Arbe-Barnes, EH ; Lander, N ; Truscott, R ; Pagan, J ; Bajel, A ; Sherwood, K ; Martin, L ; Thomas, H ; Georgiou, D ; Fostira, F ; Goldberg, Y ; Adams, DJ ; van der Biezen, SAM ; Christie, M ; Clendenning, M ; Thomas, LE ; Deltas, C ; Dimovski, AJ ; Dymerska, D ; Lubinski, J ; Mahmood, K ; van der Post, RS ; Sanders, M ; Weitz, J ; Taylor, JC ; Turnbull, C ; Vreede, L ; van Wezel, T ; Whalley, C ; Arnedo-Pac, C ; Caravagna, G ; Cross, W ; Chubb, D ; Frangou, A ; Gruber, AJ ; Kinnersley, B ; Noyvert, B ; Church, D ; Graham, T ; Houlston, R ; Lopez-Bigas, N ; Sottoriva, A ; Wedge, D ; Jenkins, MA ; Kuiper, RP ; Roberts, AW ; Cheadle, JP ; Ligtenberg, MJL ; Hoogerbrugge, N ; Koelzer, VH ; Rivas, AD ; Winship, IM ; Ponte, CR ; Buchanan, DD ; Power, DG ; Green, A ; Tomlinson, IPM ; Sampson, JR ; Majewski, IJ ; de Voer, RM (CELL PRESS, 2022-05-05)
    We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
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    "Left in limbo": Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis
    den Elzen, N ; Joseland, SL ; Saya, S ; Jonnagadla, S ; Isbister, J ; Winship, I ; Buchanan, DD (BMC, 2021-10-16)
    BACKGROUND: A diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis. METHODS: Semi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services. RESULTS: Participants' interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants' interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received. CONCLUSIONS: Our study findings highlight the variability in patients' interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.
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    No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
    Dominguez-Valentin, M ; Plazzer, J-P ; Sampson, JR ; Engel, C ; Aretz, S ; Jenkins, MA ; Sunde, L ; Bernstein, I ; Capella, G ; Balaguer, F ; Macrae, F ; Winship, IM ; Thomas, H ; Evans, DG ; Burn, J ; Greenblatt, M ; Cappel, WHDVTN ; Sijmons, RH ; Nielsen, M ; Bertario, L ; Bonanni, B ; Tibiletti, MG ; Cavestro, GM ; Lindblom, A ; Della Valle, A ; Lopez-Kostner, F ; Alvarez, K ; Gluck, N ; Katz, L ; Heinimann, K ; Vaccaro, CA ; Nakken, S ; Hovig, E ; Green, K ; Lalloo, F ; Hill, J ; Vasen, HFA ; Perne, C ; Buettner, R ; Goergens, H ; Holinski-Feder, E ; Morak, M ; Holzapfel, S ; Hueneburg, R ; Doeberitz, MVK ; Loeffler, M ; Rahner, N ; Weitz, J ; Steinke-Lange, V ; Schmiegel, W ; Vangala, D ; Crosbie, EJ ; Pineda, M ; Navarro, M ; Brunet, J ; Moreira, L ; Sanchez, A ; Serra-Burriel, M ; Mints, M ; Kariv, R ; Rosner, G ; Pinero, TA ; Pavicic, WH ; Kalfayan, P ; ten Broeke, SW ; Mecklin, J-P ; Pylvanainen, K ; Renkonen-Sinisalo, L ; Lepisto, A ; Peltomaki, P ; Hopper, JL ; Win, AK ; Buchanan, DD ; Lindor, NM ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Figueiredo, JC ; Thibodeau, SN ; Therkildsen, C ; Hansen, TVO ; Lindberg, L ; Rodland, EA ; Neffa, F ; Esperon, P ; Tjandra, D ; Moslein, G ; Seppala, TT ; Moller, P (MDPI, 2021-07)
    BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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    DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer
    Joo, JE ; Clendenning, M ; Wong, EM ; Rosty, C ; Mahmood, K ; Georgeson, P ; Winship, IM ; Preston, SG ; Win, AK ; Dugue, P-A ; Jayasekara, H ; English, D ; Macrae, FA ; Hopper, JL ; Jenkins, MA ; Milne, RL ; Giles, GG ; Southey, MC ; Buchanan, DD (MDPI, 2021-06)
    We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10-16) and young people without CRC (p = 5.8 × 10-6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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    Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer
    Jenkins, MA ; Buchanan, DD ; Lai, J ; Makalic, E ; Dite, GS ; Win, AK ; Clendenning, M ; Winship, IM ; Hayes, RB ; Huyghe, JR ; Peters, U ; Gallinger, S ; Le Marchand, L ; Figueiredo, JC ; Pai, RK ; Newcomb, PA ; Church, JM ; Casey, G ; Hopper, JL (OXFORD UNIV PRESS, 2021-04)
    It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes-people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.