Originally published as JCO Early Release 10.1200/JCO.2008.16.1281 on December 15 2008

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Role for Genetic Anticipation in Lynch Syndrome

Mef Nilbert, Susanne Timshel, Inge Bernstein, Klaus Larsen

From the Copenhagen University, Clinical Research Centre; Hereditary Nonpolyposis Colorectal Cancer Register; Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark; and the Department of Oncology; Lund University, Lund, Sweden

Corresponding author: Mef Nilbert, MD, PhD, Clinical Research Centre, Hvidovre Hospital, Kettegård Allé 30, 2650 Hvidovre, Denmark; e-mail: Mef.Nilbert{at}med.lu.se

Purpose Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum.

Patients and Methods In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation.

Results Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated.

Conclusion The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.

published online ahead of print at www.jco.org on December 15, 2008.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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