Medicine (RMH) - Research Publications

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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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    Mendelian randomisation study of smoking exposure in relation to breast cancer risk
    Park, HA ; Neumeyer, S ; Michailidou, K ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baten, A ; Freeman, LEB ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brucker, SY ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dos-Santos-Silva, I ; Dwek, M ; Eccles, DM ; Eliassen, AH ; Engel, C ; Eriksson, M ; Evans, DG ; Fasching, PA ; Flyger, H ; Fritschi, L ; Garcia-Closas, M ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Glendon, G ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Grip, M ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Han, S ; Harkness, EF ; Hart, SN ; He, W ; Heemskerk-Gerritsen, BAM ; Hopper, JL ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Jung, A ; Kaaks, R ; Kapoor, PM ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Kurian, AW ; Lacey, J ; Lambrechts, D ; LeMarchand, L ; Lo, W-Y ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; ElenaMartinez, M ; Mavroudis, D ; Meindl, A ; Menon, U ; Milne, RL ; Muranen, TA ; Nevanlinna, H ; Newman, WG ; Nordestgaard, BG ; Offit, K ; Olshan, AF ; Olsson, H ; Park-Simon, T-W ; Peterlongo, P ; Peto, J ; Plaseska-Karanfilska, D ; Presneau, N ; Radice, P ; Rennert, G ; Rennert, HS ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Schoemaker, MJ ; Schwentner, L ; Scott, C ; Shah, M ; Shu, X-O ; Simard, J ; Smeets, A ; Southey, MC ; Spinelli, JJ ; Stevens, V ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Vijai, J ; Wang, S ; Wendt, C ; Winqvist, R ; Wolk, A ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Zheng, W ; Kraft, P ; Chang-Claude, J (SPRINGERNATURE, 2021-08-02)
    BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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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, 2021-07-01)
    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, 2021-06-01)
    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, 2021-03-08)
    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.
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    Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report
    Dominguez-Valentin, M ; Crosbie, EJ ; Engel, C ; Aretz, S ; Macrae, F ; Winship, I ; Capella, G ; Thomas, H ; Nakken, S ; Hovig, E ; Nielsen, M ; Sijmons, RH ; Bertario, L ; Bonanni, B ; Tibiletti, MG ; Cavestro, GM ; Mints, M ; Gluck, N ; Katz, L ; Heinimann, K ; Vaccaro, CA ; Green, K ; Lalloo, F ; Hill, J ; Schmiegel, W ; Vangala, D ; Perne, C ; Strauss, H-G ; Tecklenburg, J ; Holinski-Feder, E ; Steinke-Lange, V ; Mecklin, J-P ; Plazzer, J-P ; Pineda, M ; Navarro, M ; Brunet Vidal, J ; Kariv, R ; Rosner, G ; Alejandra Pinero, T ; Laura Gonzalez, M ; Kalfayan, P ; Ryan, N ; Ten Broeke, SW ; Jenkins, MA ; Sunde, L ; Bernstein, I ; Burn, J ; Greenblatt, M ; Cappel, WHDVTN ; Della Valle, A ; Lopez-Koestner, F ; Alvarez, K ; Buettner, R ; Goergens, H ; Morak, M ; Holzapfel, S ; Hueneburg, R ; Doeberitz, MVK ; Loeffler, M ; Rahner, N ; Weitz, J ; Pylvanainen, K ; Renkonen-Sinisalo, L ; Lepisto, A ; Auranen, A ; Hopper, JL ; Win, AK ; Haile, RW ; Lindor, NM ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Figueiredo, JC ; Thibodeau, SN ; Therkildsen, C ; Okkels, H ; Ketabi, Z ; Denton, OG ; Rodland, EA ; Vasen, H ; Neffa, F ; Esperon, P ; Tjandra, D ; Moeslein, G ; Sampson, JR ; Evans, DG ; Seppala, TT ; Moller, P (ELSEVIER SCIENCE INC, 2020-12-01)
    PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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    CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
    Johnson, N ; Maguire, S ; Morra, A ; Kapoor, PM ; Tomczyk, K ; Jones, ME ; Schoemaker, MJ ; Gilham, C ; Bolla, MK ; Wang, Q ; Dennis, J ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Augustinsson, A ; Baynes, C ; Freeman, LEB ; Beckmann, MW ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Boeckx, B ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Burwinkel, B ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Conroy, DM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Doerk, T ; Eliassen, AH ; Engel, C ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Flyger, H ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Closas, M ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Harrington, PA ; Hart, SN ; Hooning, MJ ; Hopper, JL ; Howell, A ; Hunter, DJ ; Jager, A ; Jakubowska, A ; John, EM ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Le Marchand, L ; Linet, M ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Martens, JWM ; Mavroudis, D ; Mayes, R ; Meindl, A ; Milne, RL ; Neuhausen, SL ; Nevanlinna, H ; Newman, WG ; Nielsen, SF ; Nordestgaard, BG ; Obi, N ; Olshan, AF ; Olson, JE ; Olsson, H ; Orban, E ; Park-Simon, T-W ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Rennert, HS ; Ruddy, KJ ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Scott, C ; Shu, X-O ; Simard, J ; Smichkoska, S ; Sohn, C ; Southey, MC ; Spinelli, JJ ; Stone, J ; Tamimi, RM ; Taylor, JA ; Tollenaar, RAEM ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; van Veen, EM ; Wang, SS ; Weinberg, CR ; Wendt, C ; Wildiers, H ; Winqvist, R ; Wolk, A ; Zheng, W ; Ziogas, A ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Howie, AF ; Peto, J ; dos-Santos-Silva, I ; Swerdlow, AJ ; Chang-Claude, J ; Schmidt, MK ; Orr, N ; Fletcher, O (SPRINGERNATURE, 2021-01-26)
    BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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    Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum
    Dominguez-Valentin, M ; Sampson, JR ; Moller, P ; Seppala, TT (WILEY, 2020-07-30)
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    The Impact of a Comprehensive Risk Prediction Model for Colorectal Cancer on a Population Screening Program
    Saya, S ; Emery, JD ; Dowty, JG ; McIntosh, JG ; Winship, IM ; Jenkins, MA (OXFORD UNIV PRESS, 2020-10-01)
    Background In many countries, population colorectal cancer (CRC) screening is based on age and family history, though more precise risk prediction could better target screening. We examined the impact of a CRC risk prediction model (incorporating age, sex, lifestyle, genomic, and family history factors) to target screening under several feasible screening scenarios. Methods We estimated the model’s predicted CRC risk distribution in the Australian population. Predicted CRC risks were categorized into screening recommendations under 3 proposed scenarios to compare with current recommendations: 1) highly tailored, 2) 3 risk categories, and 3) 4 sex-specific risk categories. Under each scenario, for 35- to 74-year-olds, we calculated the number of CRC screens by immunochemical fecal occult blood testing (iFOBT) and colonoscopy and the proportion of predicted CRCs over 10 years in each screening group. Results Currently, 1.1% of 35- to 74-year-olds are recommended screening colonoscopy and 56.2% iFOBT, and 5.7% and 83.2% of CRCs over 10 years were predicted to occur in these groups, respectively. For the scenarios, 1) colonoscopy was recommended to 8.1% and iFOBT to 37.5%, with 36.1% and 50.1% of CRCs in each group; 2) colonoscopy was recommended to 2.4% and iFOBT to 56.0%, with 13.2% and 76.9% of cancers in each group; and 3) colonoscopy was recommended to 5.0% and iFOBT to 54.2%, with 24.5% and 66.5% of cancers in each group. Conclusions A highly tailored CRC screening scenario results in many fewer screens but more cancers in those unscreened. Category-based scenarios may provide a good balance between number of screens and cancers detected and are simpler to implement.
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    Morphological predictors of BRCA1 germline mutations in young women with breast cancer
    Southey, MC ; Ramus, SJ ; Dowty, JG ; Smith, LD ; Tesoriero, AA ; Wong, EEM ; Dite, GS ; Jenkins, MA ; Byrnes, GB ; Winship, I ; Phillips, K-A ; Giles, GG ; Hopper, JL (NATURE PUBLISHING GROUP, 2011-03-15)
    BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. METHODS: We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. RESULTS: The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90). CONCLUSION: Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.