The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect
| Autor: | Stefan Aretz, Jenny von Salomé, Liesbeth Spruijt, Inge Bernstein, Tom G.W. Letteboer, Theo A. M. van Os, Kristina Lagerstedt-Robinson, Magnus von Knebel Doeberitz, Encarna B. Gomez-Garcia, Verena Steinke-Lange, Sanne W. ten Broeke, Maran J. W. Olderode-Berends, Hans K. Schackert, Marta Pineda, Manon Suerink, Gabriel Capellá, Nils Rahner, Carli M. J. Tops, Mar Rodríguez-Girondo, Christoph Engel, Anja Wagner, Pål Møller, Liselotte P. van Hest, Maartje Nielsen |
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| Přispěvatelé: | Human genetics, CCA - Cancer biology and immunology, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Clinical Genetics, Human Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proband Male medicine.medical_specialty Epidemiology Colorectal cancer Penetrance DNA Mismatch Repair COLORECTAL-CANCER 03 medical and health sciences 0302 clinical medicine Cohort Effect medicine Humans HETEROGENEITY Age of Onset Aged Mismatch Repair Endonuclease PMS2 Netherlands Proportional Hazards Models RISK Models Statistical business.industry Anticipation Genetic Middle Aged medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis Confidence interval Lynch syndrome Pedigree 030104 developmental biology Oncology 030220 oncology & carcinogenesis Anticipation (genetics) Mutation Medical genetics Female Age of onset NO EVIDENCE business Demography Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] |
| Zdroj: | Ten Broeke, S W, Rodríguez-Girondo, M, Suerink, M, Aretz, S, Bernstein, I, Capella, G, Engel, C, Gomez-Garcia, E B, van Hest, L P, von Knebel Doeberitz, M, Lagerstedt-Robinson, K, Letteboer, T G W, Møller, P, van Os, T A M, Pineda, M, Rahner, N, Olderode-Berends, M J W, von Salomé, J, Schackert, H K, Spruijt, L, Steinke-Lange, V, Wagner, A, Tops, C M J & Nielsen, M 2019, ' The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect ', Cancer Epidemiology, Biomarkers & Prevention, vol. 28, no. 6, pp. 1010-1014 . https://doi.org/10.1158/1055-9965.EPI-18-0576 Cancer Epidemiology, Biomarkers & Prevention, 28, 6, pp. 1010-1014 Cancer Epidemiology, Biomarkers and Prevention, 28(6), 1010-1014 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 28(6), 1010-1014. AMER ASSOC CANCER RESEARCH Cancer Epidemiology Biomarkers and Prevention, 28(6), 1010-1014. American Association for Cancer Research Inc. Cancer Epidemiology Biomarkers & Prevention, 28(6), 1010-1014. American Association for Cancer Research Inc. Cancer epidemiology, biomarkers & prevention, 28(6), 1010-1014. American Association for Cancer Research Inc. Cancer Epidemiology, Biomarkers and Prevention, 28(6), 1010-1014. AMER ASSOC CANCER RESEARCH Cancer Epidemiology, Biomarkers & Prevention, 28, 1010-1014 ten Broeke, S W, Rodríguez-Girondo, M, Suerink, M, Aretz, S, Bernstein, I, Capella, G, Engel, C, Gomez-Garcia, E B, van Hest, L P, von Knebel Doeberitz, M, Lagerstedt-Robinson, K, Letteboer, T G W, Moller, P, van Os, T A, Pineda, M, Rahner, N, Olderode-Berends, M J W, von Salome, J, Schackert, H K, Spruijt, L, Steinke-Lange, V, Wagner, A, Tops, C M J & Nielsen, M 2019, ' The apparent genetic anticipation in PMS2-associated lynch syndrome families is explained by birth-cohort effect ', Cancer Epidemiology Biomarkers and Prevention, vol. 28, no. 6, pp. 1010-1014 . https://doi.org/10.1158/1055-9965.EPI-18-0576 |
| ISSN: | 1055-9965 |
| Popis: | Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162–4.328] for the second generation and 2.644 (95% CI, 1.082–6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648–2.619) and HR = 1.074 (95% CI, 0.406–2.842) for second and third generations, respectively]. Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition. |
| Databáze: | OpenAIRE |
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