Clinical aspects of Lynch syndrome

• Colorectal cancer is the second most common cancer in women and the third most common cancer in men worldwide, with 1.8 million new cases and almost 861000 deaths in 2018. Approximately 5–10% of the annual CRC burden can be attributed to inherited high risk germline mutations. The most common inherited colon cancer syndrome is Lynch syndrome, which accounts for up to 5% of all CRCs. Lynch syndrome displays both genotypic and phenotypic heterogeneity and can be suspected on the basis of a strong family history of colorectal- or endometrial cancer, but also of other tumors. Genetic counselling is recommended for families with Lynch syndrome, to provide the patient and family members with information about cancers risk and options for surveillance and management. In paper I we compared disease associated haplotypes in families from Sweden, Germany and France, all carrying the MLH1 mutation c.2059C>T, in order to elucidate if this is a founder mutation. When analyzing the haplotype in the families with Swedish descent, a shared region of approximately 0.9–2.8 Mb was identified. The MLH1 c.2059C>T mutation thus act as a founder in the Swedish population, but is also found in Europe, Asia and Australia, indicating that this is a recurring mutation globally albeit with a very low allele frequency. In paper II and III we investigated if genetic anticipation was part of the clinical picture in a Swedish cohort of Lynch syndrome families, as well as in a larger European cohort of PMS2 mutation carriers. In paper II, a total 1003 proven mutation carriers from 239 families with Lynch syndrome were included. An anticipation effect of 2,55 years and hazard rate of 1.33 between generations was seen in families with MSH2 mutation. In addition, an anticipation effect of 7.33 years and a hazard ration of 1.86 per generation was shown in families with PMS2 mutation. In paper III, 637 individuals from 123 families with PMS2 mutation were recruited from Netherlands, Norway, Germany, Denmark, Spain, including the Swedish PMS2 patients in paper II. Participants were assigned mutation probabilities in cases of unknown carrier status. As opposed to the result in paper II, an anticipation effect initially shown in a crude analysis was no longer statistically significant when corrections were made for gender and birth cohort. In paper IV we characterized the tumor spectrum, excluding colorectal- and endometrial cancers, in a nationwide cohort of 235 Swedish Lynch syndrome families. Data was stratified for gender, primary cancer, age, and mutated gene. Relative proportions of specific cancer types were compared to corresponding proportions in the reference population from the national Swedish Cancer Registry. Individuals of both sexes in our cohort had a higher proportion of gastric cancer, small bowel cancer and urinary tract cancer compared to the general population. In female mutation carriers, the proportion of ovarian cancer and non-melanoma skin cancer was increased compared to the general population.

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