Hereditary Micro‑Satellite Instable cancers associated with Lynch Syndrome: predictive biomarkers and novel immuno-therapeutic approaches

Inherited familial tumors are linked to distinct germline mutations that result in different syndromic phenotypes, increasing cancer risk in patients. Recent findings have unveiled new evidence of genotype-phenotype correlations and highlighted the essential role of biomolecular and immunohistochemical (IHC) analyses in pinpointing predictive markers for immune-therapy responses. Lynch Syndrome (LS), recently identified as four unique hereditary cancer syndromes, is defined by specific germline mutations in Mismatch Repair Genes MLH1, MSH2, MSH6, PMS2. It features distinctive characteristics such as the early development of visceral tumors (primarily colorectal cancer, endometrial, ovarian, urothelial) and a high incidence of synchronous and metachronous cancers. LS cancers exhibit microsatellite instability (MSI). MSI was first used as an indicator of a genetic predisposition, but it is now recognized as an essential predictive marker for therapy response to immune checkpoint inhibitors. These findings resulted in the approval of immune checkpoint inhibitors, such as anti-programmed cell death 1 (anti-PD1) or anti-programmed cell death ligand 1 (anti-PD-L1) by regulatory bodies solely based on MSI status, independent of the type of cancer. In this case, a transition to a universal LS molecular screening method for all newly diagnosed colorectal and endometrial cancers has been effectively promoted. This shift in viewpoint will necessitate a thorough examination of present guidelines, encompassing recommendations on the optimal timing and approach for the implementation of biomolecular and IHC analyses to evaluate MSI status in additional cancers associated with LS. In this review, we offer a clinical summary of the primary MSI-H/dMMR cancers linked to LS and present a detailed description of immunotherapy, recently introduced for some neoplastic entities but increasingly extended to other tumors. We additionally emphasize the absence of existing molecular screening for rarer LS-associated tumors, like sebaceous cancers, which could gain the most from universal IHC screening and contemporary immuno-therapeutic strategies.