Relevance, Pathogenesis, and Testing Algorithm for Mismatch Repair–Defective Colorectal Carcinomas

Abstract

Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder.

S3-Leitlinie – Kolorektales Karzinom

“…Die Trennschärfe einer BRAF-Mutationsanalyse zur Abgrenzung spontaner von hereditären kolorektalen Karzinomen liegt bei etwa 50 % [1067], die einer Methylierungsanalyse ist vollstän-dig (~100 %) [1068].…”

Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1

“…Furthermore, we cannot exclude confounding effects like BRAF mutations or resistance to 5-fluorouracil by microsatellite instability, which were previously shown to influence survival in colorectal cancer patients. 53,54 However, owing to the lack of material and bad DNA quality, it was not possible to assess additional genetic markers in our study cohort. In conclusion, the identification and validation of new biomarker is challenging owing to several reasons (for a detailed review see Febbo et al 55 ); therefore, our results should be evaluated together with other prognostic factors such as BRAF mutations prospectively in a larger clinical trial.…”

The Prognostic Value of Microsatellite Instability, KRAS, BRAF and PIK3CA Mutations in Stage II Colon Cancer Patients

“…Although studies have been equivocal concerning proposed survival benefit, some found that MSI is associated with better prognosis (12). Recent data support a prognostic role for combined MSI/BRAF testing in colorectal cancer (13,14).…”