Is tumor testing efficiency for Lynch syndrome different in rectal and colon cancer?

Dig Liver Dis. 2020 Dec;52(12):1503-1511. doi: 10.1016/j.dld.2020.06.002. Epub 2020 Jun 30.

Abstract

Background: Tumor testing utility in Lynch syndrome (LS) diagnosis is established.

Aims: Analyze the differences between tumor testing efficiency in rectal (RC) and colon cancer (CC).

Methods: We performed immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins (IHC-MMR) and MicroSatellite Instability analysis (MSI) on 482 unselected primary tumors: 320 CCs and 162 RCs. Samples had proficient-IHC, deficient-IHC or borderline-IHC ("patchy" expression). MSI-H borderline-IHC tumors were considered as likely MMR-deficient. Germline testing was offered to MMR-deficient patients without BRAF mutation or MLH1 promoter hypermetilation (MLH1-Hy).

Results: We identified 51/482 (10.6%) MMR-defective tumors. Multivariable analysis demonstrated a significant correlation between tumor testing results with histotype, lymph-node involvement and tumor location. In particular, RC showed a lower MMR-deficiency rate than CC (p<0.0001). Interestingly, MLH1 loss was detected in 0% RCs and 76.1% CCs, with 80% of them showing BRAF mutation/MLH1-Hy. A germline variant was detected in 12 out of 18 patients (mutation detection rate of 66.7%).

Conclusion: Tumor testing results showed molecular differences between CCs and RCs, in terms of MMR proteins expression, and presence of BRAF mutation/MLH1-Hy. MSH6 variants were the most frequent ones (50%). Although young age at diagnosis was associated with mutation detection (p = 0.045), 33.3% of LS patients were >50 years.

Keywords: Immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins; Lynch syndrome; MicroSatellite Instability analysis (MSI); Tumor testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Colonic Neoplasms / diagnosis
  • Colonic Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Methylation / genetics
  • DNA Mismatch Repair / genetics*
  • Early Detection of Cancer / methods*
  • Female
  • Genetic Testing / methods
  • Humans
  • Immunohistochemistry
  • Logistic Models
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Multivariate Analysis
  • MutL Protein Homolog 1 / genetics
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • Rectal Neoplasms / diagnosis
  • Rectal Neoplasms / genetics*

Substances

  • MLH1 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1