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Prognostic impact of ATM mutations in patients with metastatic colorectal cancer

Giovanni Randon1, Giovanni Fucà1, Daniele Rossini2

  • 1Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Via G. Venezian, 1 - 20133, Milan, Italy.

Scientific Reports
|March 1, 2019
PubMed

Insights

ATM gene mutations in metastatic colorectal cancer (mCRC) predict longer survival. Tumors with ATM mutations, indicating homologous recombination deficiency, are linked to improved overall survival in mCRC patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Homologous recombination deficiency (HRD) confers sensitivity to DNA double-strand breaks, a mechanism exploited by certain chemotherapies.
  • The ATM gene, crucial for DNA damage response, is frequently altered in colorectal cancer (CRC).
  • The prognostic and predictive value of ATM mutations in metastatic CRC (mCRC) remains underexplored.

Purpose of the Study:

  • To investigate the prognostic significance of ATM mutational status in patients with metastatic colorectal cancer (mCRC).
  • To determine if ATM mutations can serve as a predictive biomarker for treatment response or patient outcomes in mCRC.

Main Methods:

  • A multicenter study involving next-generation sequencing to analyze mutational profiles of 227 mCRC samples.
  • Correlation analysis between ATM mutational status and overall survival (OS) using statistical methods, including multivariable modeling.
  • Assessment of ATM mutation heterogeneity and its association with prognosis.

Main Results:

  • ATM mutations were identified in 15% (35/227) of the mCRC samples analyzed.
  • Patients with ATM-mutated tumors exhibited significantly longer median overall survival (64.9 months) compared to those with wild-type ATM (34.8 months).
  • ATM mutations were independently associated with improved OS in multivariable analyses, irrespective of TP53 status or tumor location. High ATM mutation heterogeneity correlated with excellent prognosis.

Conclusions:

  • ATM mutations are an independent prognostic biomarker associated with longer overall survival in patients with metastatic colorectal cancer.
  • The findings suggest that ATM mutational status could inform treatment strategies and patient stratification in mCRC.
  • Further research into ATM's role in DNA repair pathways may reveal novel therapeutic targets for mCRC.

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