Riassunto analitico
Introduction: Lynch syndrome (LS) is a nonpolyposis hereditary colorectal cancer syndrome caused by germline mutations in genes controlling the DNA Mismatch Repair System (hMLH1, hMSH2, hMSH6, hPMS2 and EPCAM). As a result of Mismatch Repair (MMR) deficiency, LS-associated cancers typically manifest microsatellite instability and immunohistochemical loss of MMR proteins. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is a clinically-defined syndrome fulfilling the “Amsterdam Criteria”, formerly introduced in 1990 to identify nonpolyposis colorectal cancer prone families to be investigated through genetic analyses. The difference between LS and HNPCC relies on the presence, in the former, of germline MMR genes mutations, whereas in the latter only clinical diagnosis is required. The reckoning of Amsterdam Criteria-positive families without LS-predisposing mutations has always constitute an intriguing and puzzling finding, whose effort of the scientific community is beginning to shed light on. Clinically-suspected LS without MMR germline mutations are categorized according to the presence or absence, in the tumor sample, of microsatellite instability and immunohistochemical expression of MMR proteins. HNPCC without germline MMR mutations and without microsatellite instability is called Familial Colorectal Cancer Type X (FCCTX): these patients display a colorectal cancer (CRC) risk increased 2-fold over the general population and lack extracolonic cancers. CRC families without MMR germline mutations, but with microsatellite instability and/or with immunohistochemical loss of MMR proteins belong to either Lynch-like syndrome (LLS) or to Sporadic MMR deficient colorectal cancer. Lynch-like syndrome causes increases in colorectal and extracolonic cancer risk, respectively 2,1 and 1,7-fold over the general population. Sporadic MMR deficient colorectal cancer does not significantly augment the risk of cancer.
Aim of the study: The aim of the present study is to describe the results of a long-term follow up of HNPCC families without germline MMR mutations, focusing on the occurrence of tumors during the period of observation.
Materials and methods: 15 families with HNPCC and without germline mutations were identified in our Health Care District through a specialized colorectal cancer registry. A retrospective, observational study on tumor onset in these families was designed, analyzing data from the year of clinical diagnosis to 31/12/2017. Information about cancer onset was collected through direct interviews and informatic devices. We calculated the relative risk (RR), using as the reference population the Tuscany Regional Registry of 2009. For risk analysis, the study group (hence also called HNPCC group) was divided in one subgroup, the FCCTX subgroup. No LLS subgroup was made due to the poor number of members.
Results: Of the 15 HNPCC studied, 8 were FCCTX, 2 were LLS, 1 was a suspected epigenetic Lynch syndrome, and 4 were not further categorizable. During the period of observation (26 years in average), 114 neoplasms developed, of which 37 were CRC. CRCs were right-sided in 39% of the HNPCC group and in 33% of FCCTX. The RR of CRC was significantly higher in the study group than in the general population (RR for the HNPCC group 2,06; 95% confidence interval [CI]: 1,17-3,62) (RR for the FCCTX subgroup 2,10; 95% CI: 1,09-4,04). Considering age groups, the RR of CRC in the HNPCC group showed a bimodal distribution, reaching a significant peak in the age group 51-60 and 71-80. A slight reduction in the risk for extra HNPCC tumors was observed in the study group. No difference between the HNPCC group and the general population was found in overall colorectal cancer survival.
Conclusions: The risk of colorectal cancer in HNPCC families without germline MMR mutations is higher than that of the general population. This result confirms the need for dedicated surveillance strategies for these patients.
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