Extra-colonic cancers in Lynch Syndrome

Abstract

Lynch Syndrome (LS) is the most common of the hereditary colorectal cancer (CRC) syndromes. It is caused by germ-line mutations in one of the four mismatch repair (MMR) genes MLHl, MSH2, MSH6 or PMS2. Mutations in one of these genes also predispose to several other types of cancer, among these is endometrial cancer the most common. Most estimates on cancer risk associated with MMR mutation have so far been based on retrospective studies. Identification of families with deleterious MMR mutation is of importance, as surveillance may lead to early detection and cure of cancer. The identification of mutation carriers is today mainly based on evaluation of family history of cancers, classification of the families according to the Amsterdam and/or Bethesda clinical criteria and genetic testing of tumour tissue and blood. This work is challenged by the fact that many families with MMR mutations do not fulfill the clinical criteria. The overall aim of the study was to describe extra-colonic cancers occurring in known MMR mutation carriers, and to calculate the sensitivity of the clinical criteria to identify families with deleterious MMR mutation. By prospectively following women with demonstrated MMR mutation and women belonging to families with aggregation of cancers suggestive of LS but without identified mutation we observed that increased risk of endometrial cancer may be restricted to MMR mutation carriers. Prostate cancer was not known to be associated with LS. Immunohistochemical analysis (IRC) of tumour tissue from prostate cancers in known MMR mutation carriers demonstrated that the tumours were caused by the mutation. In the series examined prostate cancer occured with a higher frequency, at a younger age and more advanced stage than expected in a similar group of men without known hereditary predisposition to prostate cancer. The Kaplan-Meier algorithm was used to calculate crude and disease specific survival in female MMR mutation carriers who had contracted ovarian cancer. Eighty-one point five percent of the ovarian cancers were diagnosed as FIOO stage 1 or 2, and 10-year ovarian cancer specific survival independent of staging was 80.6%. This is in contrast to what has been reported for sporadic ovarian cancer and ovarian cancer caused by mutation in BRCAl or BRCA2, where 10-year survival is less than 50%. By reclassifying all families who had been demonstrated to have a MMR mutation by November 2009 according to the original and revised Amsterdam and Bethesda clinical criteria we found that less than half of families with MSH6 mutations would have been identified by the revised Amsterdam criteria. The combined findings in the studies comprising this thesis emphasize the importance of regarding LS not solely as a CRC syndrome, but as a multi organ cancer syndrome. They also confirm that the clinical criteria in use today to select families for genetic testing will fail to identify a number of mutation carriers and reflect that the different MMR genes may have different expression and penetrance.