Epidemiology
The Prospective Lynch Syndrome Database (PLSD) was a Norwegian initiative for European collaboration which has become a worldwide ongoing effort (1). PLSD has published colorectal cancer and cancer incidences in any organ in carriers of pathogenic MMR variants, and survival when cancers occur, in carriers subjected to follow-up and treatment as internationally advocated, including regular colonoscopy (1). In the InSiGHT variant database (2) all known MMR variants scored as pathogenic or non-pathogenic are included (see also 'MMR CANCER RISK' in the database, or directly at www.plsd.eu.
The four inherited MSI cancer syndromes are different at the group level with respect to penetrance (incidence of disease), expressivity (cancer in which organ), mortality and sex (1). No one has an 'average sex' and/or a pathogenic variant of an 'average gene'. Consequently, averages for penetrance, incidences and survival in the four different forms of dominantly inherited MSI cancer syndromes and without taking account of sex, are valid for no one. The four hereditary MSI cancer syndromes entail an increased risk of cancer in 13 different organs: The colon, rectum, small bowel, stomach, bile duct, pancreas, prostate, endometrium, ovaries, urinary bladder, ureter, brain and for osteosarcomas. Colorectal cancer is not the most frequent cause of death. Gynaecological cancer is frequent in women, while urinary tract/prostate cancer is frequent in men. Ovarian cancer is thought to be a variant of endometrial cancer.
The PLSD collaboration has reported that survival in the inherited MSI cancers that have onset relatively early in life, such as colorectal cancer, endometrial and ovarian cancer, has been improved due to early diagnosis and better treatment. In addition to this, we now have immunotherapy. Patients who are cured may live on to contract cancers in other organs. Such later cancers in other organs often result in poorer survival than in patients who were previously cancer-free, and this means that most fatalities in inherited MSI cancers are observed in other organs than the colon, endometrium and ovaries (1). Cancer in persons with pathogenic MMR variants will generally entail stochastic variables (1): those who have had cancer previously do not appear to have a significantly increased risk of new cancer, either in the same or other organs.
Cancer in persons with pathogenic MMR variants will generally entail stochastic variables: those who have had cancer previously do not appear to have a significantly increased risk of new cancer, either in the same or other organs
Colonoscopy has not substantially reduced the incidence of inherited MSI cancer. If the adenoma-carcinoma paradigm were true, then removing adenomas detected on colonoscopy should lead to reduced incidence of colorectal cancer in the risk groups. This is reportedly what happens in path_PMS2 carriers, but not in path_MLH1, path_MSH2 and path_MSH6 carriers (1,3). This may reflect the fact that healthy carriers have microscopic precursors of MSI cancer in the colonic crypts. These precursors produce neopeptides which attract immune cells, and the precursor is removed by the immune response. On the other hand, MSI cancer gives rise to neopeptides which prevent the HLA system and the immune cells from 'seeing' the tumour. Modern immunotherapy can inhibit 'unbeneficial' neopeptides from the MSI cancer tumours so that the HLA system is not prevented from removing the tumour. The fact that the immune system may also be able to remove established colorectal cancer may explain why in some groups colonoscopy does not lead to a reduced incidence of colorectal cancer. Some of the cases identified through screening may have been removed by the patient's own immune system before the cancer led to clinical symptoms if it had not been removed. This may have offset the preventive effect of removing some precursors of cancer. Immunotherapy facilitates the host immune system's ability to remove MSI tumours and research is now focusing on how the host HLA system may participate in this process with a view to developing vaccines against MSI cancers.
Recent research indicates that colonoscopy at least every third year prevents cancer that develops through a detectable adenoma in the colonic mucosa. However, not all cancers have a macroscopically detectable early stage without infiltrating cell growth, and this may explain why not all cancers can be prevented by screening. When the occurrence of cancer is not reduced by colonoscopy, the reason may be that some of the tumours that are removed by colonoscopy would have been later removed by the patient's immune system unnoticed by the patient.