N08: The Apparent Genetic Anticipation In PMS2-Associated Lynch Syndrome Families Is Explained By Birth-Cohort Effect

S. W. ten Broeke1, M. Rodríguez-Girondo2, M. Suerink1, Aretz3, 4, I. Bernstein5, 6, G. Capellá7, C. Engel8, E. Gomez Garcia9. L. P. van Hest10, M. von Knebel Doeberitz11.12, K. Lagerstedt-Robinson13, T. G. W. Letteboer14, P. Møller15, 16, 17, T. A. van Os18, M. Pineda7, N.Rahner19, M. J. W. Olderode-Berends20, J. von Salomé13, H. K. Schackert21, L. Spruijt22, V. Steinke-Lange23, A. Wagner24, C. M. J. Tops1, M. Nielsen1

1 – Department of Clinical Genetics Leiden University Medical Center, Leiden, The Netherlands. 2 – Department of Medical Statistics Leiden University Medical Center, Leiden, The Netherlands. 3 – Institute of Human Genetics University of Bonn, Bonn, Germany, 4 – Center for Hereditary Tumor Syndromes University Hospital Bonn, Germany. 5 – The Danish HNPCC-register Hvidovre Hospital, Denmark. 6 – Surgical department Aalborg University Hospital, Aalborg, Denmark. 7 – Hereditary Cancer Program. Catalan Institute of Oncology, IDIBELL, ONCOBELL, CIBERONC, L’Hospitalet de Llobregat, Barcelona, Spain. 8 – Leipzig University, Leipzig, Germany. 9 -Maastricht University Medical Center Maastricht, Maastricht, The Netherlands. 10 – Department of Clinical Genetics VU University Medical Center, Amsterdam, The Netherlands. 11 – Department of Applied Tumor Biology Institute of Pathology, University of Heidelberg, Heidelberg, Germany. 12 -Clinical Cooperation Unit Applied Tumor Biology German Cancer Research Center (DKFZ), Heidelberg, Germany. 13 – Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 14 – Department of Clinical Genetics University Medical Center, Utrecht, The Netherlands. 15 – Research Group Inherited Cancer Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Norway. 16 – Department of Tumor Biology Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Norway. 17 – Center for Hereditary Tumors HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany. 18 – Department of Clinical Genetics Academic Medical Center, Amsterdam, The Netherlands. 19 – Heinrich-Heine-University Medical Faculty, Institute of Human Genetics, Düsseldorf, Germany. 20 – University of Groningen University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 21 – Department of Surgical Research Technische Universität Dresden, Dresden, Germany. 22 – Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands. 23 – Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, 80336 Munich, Germany. 24 – Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

 

Aim: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer (CRC) penetrance compared to other Lynch syndromes. However, age at CRC 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 230 European PMS2 families.

Method: 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 CRC. 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 CRCs, were analyzed. When compared to the first generation, the crude Hazard Ratio (HR) for anticipation was 2.242 (95%CI: 1.162-4.328) for the second 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).

Conclusion: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most plausible explanation for observed younger CRC diagnosis in subsequent generations, particularly since there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome.

Top