Tumor analysis of MMR genes in Lynch‐like syndrome: Challenges associated with results interpretation

• Published in: Cancer medicine (Malden, MA) MA), 2024-04, Vol.13 (7), p.e7041-n/a
• Main Authors: Rofes, Paula, Dueñas, Núria, Valle, Jesús, Navarro, Matilde, Balmaña, Judith, Ramón y Cajal, Teresa, Tuset, Noemí, Castillo, Carmen, González, Sara, Brunet, Joan, Capellá, Gabriel, Lázaro, Conxi, Pineda, Marta
• Format: Article
• Language: English
• Subjects: Brain Neoplasms; clinical management; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - pathology; Demographics; DNA methylation; DNA Mismatch Repair - genetics; Endometrial cancer; Family medical history; Gene frequency; Genes; Genetic disorders; Genetic testing; Germ-Line Mutation; Humans; Lynch syndrome; Lynch‐like syndrome; mismatch repair genes; mismatch repair‐deficiency; Neoplastic Syndromes, Hereditary; Ovarian cancer; Small intestine; tumor testing; Tumors
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.7041

Background Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch‐like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in a variable range of LLS‐associated tumors. Moreover, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated with the implementation of tumoral MMR gene testing in routine workflows. Methods Here, we present the clinical characterization of 229 LLS patients. MMR gene testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥5% and ≥10%). Results and Discussion More biallelic somatic events were identified at VAF ≥ 5% than ≥10% (35.9% vs. 25.6%), although the rate of nonconcordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases. Biallelic somatic MMR inactivation has been reported in a variable range of LLS‐associated tumors. More biallelic somatic events are identified with a lower VAF threshold, although the rate of nonconcordant results regarding immunohistochemical pattern increase. Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases.