Medicine (RMH) - Research Publications

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    Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)
    Ye, Z ; Li, S ; Dite, GS ; Nguyen, TL ; MacInnis, RJ ; Andrulis, IL ; Buys, SS ; Daly, MB ; John, EM ; Kurian, AW ; Genkinger, JM ; Chung, WK ; Phillips, K-A ; Thorne, H ; Winship, IM ; Milne, RL ; Dugue, P-A ; Southey, MC ; Giles, GG ; Terry, MB ; Hopper, JL (AMER ASSOC CANCER RESEARCH, 2022-03-01)
    UNLABELLED: We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk. PREVENTION RELEVANCE: Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum.
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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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    Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group.
    Guerrini-Rousseau, L ; Masliah-Planchon, J ; Waszak, SM ; Alhopuro, P ; Benusiglio, PR ; Bourdeaut, F ; Brecht, IB ; Del Baldo, G ; Dhanda, SK ; Garrè, ML ; Gidding, CEM ; Hirsch, S ; Hoarau, P ; Jorgensen, M ; Kratz, C ; Lafay-Cousin, L ; Mastronuzzi, A ; Pastorino, L ; Pfister, SM ; Schroeder, C ; Smith, MJ ; Vahteristo, P ; Vibert, R ; Vilain, C ; Waespe, N ; Winship, IM ; Evans, DG ; Brugieres, L (BMJ, 2022-06-29)
    BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.
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    Health professionals' views and experiences of the Australian moratorium on genetic testing and life insurance: A qualitative study.
    Dowling, G ; Tiller, J ; McInerney-Leo, A ; Belcher, A ; Haining, C ; Barlow-Stewart, K ; Boughtwood, T ; Gleeson, P ; Delatycki, MB ; Winship, I ; Otlowski, M ; Jacobs, C ; Keogh, L ; Lacaze, P (Springer Science and Business Media LLC, 2022-11)
    Australian life insurance companies can legally use genetic test results in underwriting, which can lead to genetic discrimination. In 2019, the Financial Services Council (Australian life insurance industry governing body) introduced a partial moratorium restricting the use of genetic testing in underwriting policies ≤ $500,000 (active 2019-2024). Health professionals (HPs), especially clinical geneticists and genetic counsellors, often discuss the implications of genetic testing with patients, and provide critical insights into the effectiveness of the moratorium. Using a sequential explanatory mixed methods design, we interviewed 23 Australian HPs, who regularly discuss genetic testing with patients and had previously completed an online survey about genetic testing and life insurance. Interviews explored views and experiences about the moratorium, and regulation, in greater depth. Interview transcripts were analysed using thematic analysis. Two key themes emerged from views expressed by HPs during interviews (about matters reported to or observed by them): 1) benefits of the moratorium, and 2) concerns about the moratorium. While HPs reported that the moratorium reassures some consumers, concerns include industry self-regulation, uncertainty created by the temporary time period, and the inadequacy of the moratorium's financial limits for patients' financial needs. Although a minority of HPs felt the current industry self-regulated moratorium is an adequate solution to genetic discrimination, the vast majority (19/23) expressed concern with industry self-regulation and most felt government regulation is required to adequately protect consumers. HPs in Australia are concerned about the adequacy of the FSC moratorium with regards to consumer protections, and suggest government regulation is required.
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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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    Population DNA screening for medically actionable disease risk in adults.
    Lacaze, PA ; Tiller, J ; Winship, I ; DNA Screen Investigator Group, (Wiley, 2022-04-04)
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    Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing
    Southey, MC ; Dowty, JG ; Riaz, M ; Steen, JA ; Renault, A-L ; Tucker, K ; Kirk, J ; James, P ; Winship, I ; Pachter, N ; Poplawski, N ; Grist, S ; Park, DJ ; Pope, BJ ; Mahmood, K ; Hammet, F ; Mahmoodi, M ; Tsimiklis, H ; Theys, D ; Rewse, A ; Willis, A ; Morrow, A ; Speechly, C ; Harris, R ; Sebra, R ; Schadt, E ; Lacaze, P ; McNeil, JJ ; Giles, GG ; Milne, RL ; Hopper, JL ; Nguyen-Dumont, T (NATURE PORTFOLIO, 2021-12-09)
    Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1-16.2] for BRCA1, 4.0 [1.9-9.1] for BRCA2, 3.4 [1.4-8.4] for ATM and 4.3 [1.0-17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.
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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.