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The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect
- Source :
- 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
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 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]
Subjects
Details
- Language :
- English
- ISSN :
- 10559965
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....0beddab517e53f3ad2c205e858456c07