The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect.

Ten Broeke SW1, Rodríguez-Girondo M2, Suerink M3, Aretz S4, Bernstein I5, Capella G6, Engel C7, Gomez-Garcia EB8, van Hest LP9, von Knebel Doeberitz M10, Lagerstedt-Robinson K11, Letteboer TGW12, Møller P13, van Os TAM14, Pineda M15, Rahner N16, Olderode-Berends MJW17, von Salomé J18, Schackert HK19, Spruijt L20, Steinke-Lange V21, Wagner A22, Tops CMJ23, Nielsen M24.

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Abstract

BACKGROUND:

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 152 European PMS2 families.

MATERIAL:

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).

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 CRC diagnosis in subsequent generations, particularly since 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.