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Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer

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|February 1, 2018
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Tumour-infiltrating lymphocyte (TIL) and DNA mismatch repair (dMMR) status in colorectal cancer independently predict outcomes. Combined TIL/MMR classification offers superior prognostication compared to genomic or transcriptomic subtypes, identifying distinct patient groups.

Keywords:
colorectal carcinomaimmune responsemolecular pathologytumour markers

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Area of Science:

  • Oncology
  • Cancer Research
  • Immunology

Background:

  • Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are key prognostic factors in colorectal cancer.
  • While correlated, their independent predictive value and combined prognostic significance relative to molecular subtypes were unclear.

Purpose of the Study:

  • To investigate the prognostic significance of combined TIL/MMR classification in stage II/III colorectal cancer.
  • To compare the predictive power of TIL/MMR status against major genomic and transcriptomic subtypes.

Main Methods:

  • A prospective cohort of 1265 patients with stage II/III colorectal cancer were assessed for TIL/MMR status and common mutations.
  • Consensus molecular subtype (CMS) was determined for a subset of cases.
  • Disease-free survival (DFS) was evaluated and validated in an independent cohort of 602 patients.

Main Results:

  • Four TIL/MMR subtypes were identified: TIL-low/proficient-MMR (pMMR), TIL-high/pMMR, TIL-low/dMMR, and TIL-high/dMMR.
  • TIL-low/dMMR and TIL-low/pMMR tumours showed significantly poorer 5-year DFS compared to TIL-high/dMMR.
  • TIL/MMR classification proved a more significant predictor of prognosis than standard high-risk features and superior to genomic (dMMR, BRAF/KRAS) and transcriptomic (CMS) subtypes.

Conclusions:

  • Combined TIL/MMR classification effectively identifies distinct prognostic subgroups in stage II/III colorectal cancer.
  • The prognostic impact of dMMR is contingent on TIL levels.
  • TIL/MMR-based prognostication surpasses that of traditional histopathological, genomic, and transcriptomic classifications.