{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMSH2 is a central component of the DNA mismatch repair (MMR) system that safeguards genomic integrity by detecting and initiating repair of replication errors. Germline inactivation of MSH2 predisposes individuals to Lynch syndrome, which is characterized by an elevated risk for colorectal, endometrial, and other cancers. In this context, accurate cancer risk estimates are essential for clinical management and surveillance of affected families."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, MSH2 functions by forming heterodimers with partner proteins such as MSH6 and MSH3 to recognize mismatches and insertion/deletion loops. In addition, it coordinates with other repair factors like hMYH to correct oxidatively damaged bases and interacts with key signaling kinases—including ATR—to initiate downstream phosphorylation events essential for cell cycle checkpoint activation. Moreover, posttranscriptional regulation by microRNAs (for example, miR-21) can downregulate MSH2 expression, thereby influencing both the repair capacity and chemosensitivity of tumor cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathogenic mutations in MSH2—including point mutations, deletions and rearrangements—result in loss of protein function and the subsequent development of microsatellite instability and a hypermutator phenotype that drives tumorigenesis. Such inactivation not only promotes an increased risk for colorectal and endometrial cancers but is also linked to syndromic presentations such as Muir–Torre syndrome, and has been implicated in the hypermutated subsets of other malignancies including prostate cancer. The identification of founder mutations and the characterization of MSH2 mutation spectra have enhanced genetic testing, risk stratification, and family counseling in Lynch syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct role in mismatch correction, MSH2 has been pivotal in refining diagnostic protocols and risk assessments for hereditary cancers. Studies combining immunohistochemistry, microsatellite instability testing, and comprehensive gene dosage analyses have underscored the importance of MSH2 status for both prognostication and therapeutic decision‐making. These investigations, which also explore alternate splicing, epigenetic modifications and crosstalk with other repair pathways, have broadened our understanding of MSH2 biology and illuminated its impact on tumor sensitivity to chemotherapeutics and immunotherapy. Together with insights derived from mutation screening and founder effect analyses, this body of work reinforces the value of incorporating MSH2 functional status into clinical algorithms for the management of Lynch syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Valérie Bonadona, Bernard Bonaïti, Sylviane Olschwang, et al. 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