Strategies for Lynch syndrome identification in selected and unselected gynecological cancers

Background Endometrial carcinoma represents a sentinel cancer for Lynch syndrome (LS) identification. It is crucial to highlight how other types of tumors can arise in the gynecological tract acting as sentinel tumors in LS patients. Up to now, no established LS patient management strategy has incorporated the presence of these additional candidate sentinel tumors to improve the prevention and management of LS tumors. Methods In order to investigate the involvement of the most frequent gynecological cancers in gynecological cancers, we studied different subsets of gynecological cancers using both somatic approaches, including mismatch repair (MMR) gene immunohistochemical expression, microsatellite instability, and germline analyses ofMSH2, MSH6, MLH1, PMS2 and EPCAM genes. A total of 261 patients referring to the Cancer Genetic Counselling Service of our institution were included in the study. In detail, our series was composed of 131 patients affected by uterus cancers including endometrial, isthmus and non-HPV endocervical carcinomas, 113 patients affected by ovarian cancers and 17 patients affected by synchronous endometrial/ovarian carcinomas (SEOC). In addition, we studied 115 cases of endometrial cancers identified by 2 years of universal testing (endometrial cancers/UTs) using IHC analysis of four MMR proteins. Results and conclusions The incidence of MMR defective gynecological cancers ranged from 7.1 to 47.1% depending on cancer site and selection. LS patients carriers of pathogenetic MMR variants were identified in 19.8% of uterus cancers, 35.3% of SEOC, 4.4% of ovarian cancers. In addition, pathogenetic MMR variants were identified in 4.3% of endometrial cancers/universal testing investigated with universal screening. In conclusion, gynecological cancers are heavily involved in LS and our study shows that MMR screening using immunohistochemical pattern and MSI analysis of endometrial and ovarian cancers as well as of rare entities such as non-HPV related endocervical cancers and synchronous endometrial and ovarian cancers are sentinels for LS. Tumor testing approach improves early identification of MMR defective gynecological cancers and this is an effective strategy to detect high-risk patients and to offer them and their relatives personalized cancer prevention.