Comprehensive characterization of MCL-1 in patients with colorectal cancer: Expression, molecular profiles, and outcomes.

in International journal of cancer by Pooja Mittal, Francesca Battaglin, Yasmine Baca, Joanne Xiu, Alex Farrell, Shivani Soni, Jae Ho Lo, Lesly Torres-Gonzalez, Sandra Algaze, Priya Jayachandran, Karam Ashouri, Alexandra Wong, Wu Zhang, Jian Yu, Lin Zhang, Benjamin A Weinberg, Emil Lou, Anthony F Shields, Richard M Goldberg, John L Marshall, Sanjay Goel, Indrakant K Singh, Heinz-Josef Lenz

TLDR

  • The study examines the association of MCL-1 expression with molecular features in CRC and findings suggest it is a potential biomarker and modulator of antitumor immunity.
  • Higher MCL-1 expression is associated with favorable clinical outcomes in CRC cohorts and is characterized by distinct immune biomarkers and TME.

Abstract

Myeloid cell leukemia 1 (MCL-1) is a member of the B-cell lymphoma 2 protein family and has anti-apoptotic functions. Deregulation of MCL-1 has been reported in several cancers, including lung and breast cancer. In the present study, the association of MCL-1 expression with molecular features in colorectal cancer (CRC) has been highlighted. CRC samples from Caris Life Sciences (Phoenix, AZ) were analyzed using NextGen DNA sequencing, whole transcriptome sequencing, whole exome sequencing, and immunohistochemistry (IHC); and stratified based on MCL-1 expression as top quartile MCL-1(Q4) and bottom quartile MCL-1(Q1). Immune cell infiltration (CI) in the tumor microenvironment (TME) was measured using RNA deconvolution analysis (QuanTIseq). MCL-1tumors were associated with an increased rate of programmed death ligand 1 IHC, higher T cell-inflamed signature, interferon score, microsatellite instability-high and tumor mutational burden-high status. MCL-1was associated with higher mutation rates of BCOR, TP53, KMT2D, ASXL1, KDM6A, ATM, MSH6, SPEN, KRAS, STK11, GNAS, RNF43, and lower mutation rates of CDKN1B, NRAS, and APC, and copy number amplifications in several genes. MCL-1TME had higher CI of M1 and M2 macrophages, B cells, natural killer cells, neutrophils, and T-regulatory cells infiltration, and lower CI of myeloid dendritic cells. Higher MCL-1 expression is significantly associated with favorable clinical outcomes in CRC cohorts. Our data showed a strong correlation between MCL-1 and distinct immune biomarkers and TME CI in CRC. Our findings suggest MCL-1 is a potential modulator of antitumor immunity, TME, and biomarker in CRC.

Overview

  • The study aims to explore the association of Myeloid cell leukemia 1 (MCL-1) expression with molecular features in colorectal cancer (CRC).
  • The study analyzed CRC samples using NextGen DNA sequencing, whole transcriptome sequencing, whole exome sequencing, and immunohistochemistry (IHC) and stratified them based on MCL-1 expression as top quartile MCL-1(Q4) and bottom quartile MCL-1(Q1).
  • The primary objective is to identify the relationship between MCL-1 expression and clinical outcomes in CRC cohorts.

Comparative Analysis & Findings

  • MCL-1 tumors were associated with an increased rate of programmed death ligand 1 IHC, higher T cell-inflamed signature, interferon score, microsatellite instability-high, and tumor mutational burden-high status.
  • MCL-1 was associated with higher mutation rates of BCOR, TP53, KMT2D, ASXL1, KDM6A, ATM, MSH6, SPEN, KRAS, STK11, GNAS, RNF43, and lower mutation rates of CDKN1B, NRAS, and APC, and copy number amplifications in several genes.
  • MCL-1 TME had higher CI of M1 and M2 macrophages, B cells, natural killer cells, neutrophils, and T-regulatory cells infiltration, and lower CI of myeloid dendritic cells.

Implications and Future Directions

  • Higher MCL-1 expression is significantly associated with favorable clinical outcomes in CRC cohorts, suggesting a potential role in promoting antitumor immunity.
  • The study's findings highlight the importance of MCL-1 as a biomarker for CRC and its potential association with distinct immune biomarkers and TME.
  • Future studies could explore the therapeutic potential of targeting MCL-1 in CRC, particularly in combination with immunotherapies, to enhance antitumor immunity and improve clinical outcomes.
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