Identification of Squamous Cell Lung Carcinoma Mutations Opens Doors for Targeted Therapies

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(ChemotherapyAdvisor) –  The first comprehensive genome-wide analysis of squamous cell lung carcinoma tumors has revealed that despite a high degree of mutational heterogeneity from patient to patient, most patients' tumors contain mutations targeted by existing drugs, according to a new study published in Nature

“We found that almost 75% of the patients' cancers have mutations that can be targeted with existing drugs – drugs that are available commercially or for clinical trials,” reported Matthew Meyerson, MD, PhD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, and collaborators from the nationwide Cancer Genome Atlas consortium.

The study “will change the landscape for squamous cell carcinoma,” a disease that represents 30% of lung cancer cases and for which there are currently no specifically-targeted therapies, Dr. Meyerson concluded.

The study of tumor and non-tumor cells from 178 patients diagnosed with squamous cell carcinoma of the lung found that most patients' tumors contain recurring mutations at 18 gene loci. Almost all of the tumors contained TP53 mutations. TP53 is involved in DNA repair, the researchers noted.

However, there was marked variation in the particular suites of tumor gene mutations seen from patient to patient, the authors noted – suggesting that genomic sequencing and personalized therapies might well become standard fare for patients diagnosed with this type of lung cancer.

“We show that the tumor type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor,” they wrote. “We found statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene.”

EGFR amplifications were identified in 7% of cases, “as were two instances of the Leu861Gln EGFR mutation, which confers sensitivity to erlotinib and gefitinib,” the authors noted.

“The presence of new potential therapeutic targets in lung SQCC was suggested by the observation that 96% (171 out of 178) of tumors contain one or more mutations in tyrosine kinases, serine/threonine kinases, phosphatidylinositol-3-OH kinase (PI(3)K) catalytic and regulatory subunits, nuclear hormone receptors, G-protein-coupled receptors, proteases and tyrosine phosphatases,” they wrote.

The tumors also share mutations with head and neck squamous cell carcinomas.

“This reinforces something we've been seeing in a lot of our cancer genomics work,” said Richard K Wilson, PhD, director of the Genome Institute at Washington University in Washington, DC. “It's really less about what type of tissue the tumor arises in – lung, breast, skin, prostate – and more about what genes and pathways are affected.”

An estimated 400,000 people die each year from squamous cell lung carcinoma. It is strongly associated with tobacco smoking; smokers represent 90% of patients with this type of lung cancer.

The Cancer Genome Atlas project is a consortium of genetic sequencing programs across the US, funded by the US National Cancer Institute and US National Human Genome Research Institute, at the National Institutes of Health (NIH).


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