Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Lam, Anne-Sophie van der Werf-’ t; Terlouw, Diantha; Tops, Sophie; M, Kan; Hest, Liselotte P. van; Duijkers, Floor A.M.; Wagner, Anja; Eikenboom, Ellis L.; Letteboer, Tom G.W.; Jong, Mirjam M. de; Broeke, Sanne W. Bajwa ten; Bleeker, Fonnet E.; Gómez-García, Encarna B.; Wind, Niels de; Wezel, Tom van; Morreau, Hans; Suerink, Manon; Nielsen, Maartje

doi:10.1016/j.modpat.2023.100240

Cited by 6 publications

(1 citation statement)

References 60 publications

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“…In 12 patients, tumors also showed negative or weak staining of the MSH2 protein. No germline MSH2 variant was identified, and in cases where tumor reanalysis was feasible, no explanatory MSH3 variants were found, consistent with previous findings reported by our research group 18 . The MSH6 variants in this study were detected as part of the clinical genetic diagnostic procedure.…”

Section: Methodssupporting

confidence: 91%

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

van der Werf‐'t Lam,

Rodriguez‐Girondo,

Villasmil

et al. 2024

Genes Chromosomes & Cancer

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BackgroundThis study investigates the potential influence of genotype and parent‐of‐origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease‐causing MSH6 germline variants.Patients and MethodsA cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross‐validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC).ResultsNo significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77–1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43–1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46–0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52–1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65–1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64–1.19).Discussion and ConclusionNo evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

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Section: Methodssupporting

confidence: 91%

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

van der Werf‐'t Lam,

Rodriguez‐Girondo,

Villasmil

et al. 2024

Genes Chromosomes & Cancer

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MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence

Shia,

Sanchez-Vega,

Cho

et al. 2024

Familial Cancer

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Mismatch repair deficiency: how reliable is the two‐antibody approach? A national real‐life study

Vink‐Börger,

den Bakker,

Voorham

et al. 2024

Histopathology

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AimsTraditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach.Methods and ResultsWe performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used.ConclusionIn general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs.

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Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Cited by 6 publications

References 60 publications

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence

Mismatch repair deficiency: how reliable is the two‐antibody approach? A national real‐life study

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