Role for Genetic Anticipation in Lynch Syndrome

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

Translation and adaptation of the genetic counselling outcome scale (GCOS-24) for use in Denmark

Outcome measurement in clinical genetics is challenging. Robust outcome measures are needed to provide evidence to support service development within genetic counseling. The Genetic Counselling Outcome Scale (GCOS-24), a Patient Reported Outcome Measure (PROM), was developed in English and validated with clinical genetics patients in the British NHS. This study reports the translation and adaptation of the GCOS-24 for use in Denmark. GCOS-24 was translated and back translated, supervised by an expert committee. Feedback on the first version was collected from genetic counseling patients in qualitative interviews focusing on instructions for use, response options and specific items considered semantically difficult. After further adjustment the adapted and translated version was administered to a second sample of patients, with responses analyzed using descriptive statistics. Eighteen interviews were conducted, and led to adjustment of item wording. Sixty-one patients completed the final version GCOS-24dk. Internal consistency is good (Cronbach's α =0.79), with an acceptable number of missing responses and no floor or ceiling effect observed. GCOS-24 has been successfully translated and adapted for use in a Danish setting. The study confirms the feasibility of local adaptation of patient reported outcome measures and stresses the importance of adaptation, even across quite similar populations and health care systems