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Squamous cell carcinoma of lung identified as distinct molecular subtype
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CHICAGO — Squamous cell carcinoma of the lung is a distinct molecular subtype of lung cancer, which potentially could be targeted by distinct molecular therapies, according to results of a molecular analysis study.
Prior studies suggested that one-third of patients with non–small cell lung cancer were diagnosed with squamous cell carcinoma histology.
To follow up on those results, Ramaswamy Govindan, MD, of the division of medical oncology at Washington University School of Medicine, and colleagues enrolled 178 previously untreated patients with stage I-III squamous cell carcinoma of the lung.
Surgically resected samples from these patients were analyzed by The Cancer Genome Atlas for DNA, RNA, and miRNA sequencing, as well as DNA copy number profiling, quantification of mRNA expression and promoter methylation.
More than 30 sites of significant somatic copy number alteration were identified in the study sample. The researchers said exome sequencing of 178 lung squamous cell carcinoma vs. matched normal samples revealed 13 significantly mutated genes with a false discovery rate of less than 0.01 and high expression levels, including TP53, CDKN2A, PTEN, KEAP1 and NFE2L2.
Along with widespread loss of TP53 and CDKN2A, researchers identified alterations in the NFE2L2/KEAP1 pathways in 35% of analyzed tumors, whereas alterations to the PI3K/AKT pathways were found in 43% of tumors. MRNA expression profiling revealed four distinct expression subtypes, each augmented with distinct mutations and significant somatic copy number alterations, including: classical (37%), comprised of NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased global methylation and the highest rate of tobacco use; basal (24%), comprised of alterations in FGFR kinases; secretory (24%), which included PDGFRA alterations; and primitive (15%), which included RB1 mutations.
In addition, rearrangements of several acknowledged tumor suppressors were detected by whole-genome shotgun sequencing of 20 tumor/normal pairs and confirmed by RNA sequencing, including PTEN, RB1, NOTCH1, NF1 and CDKN2A.
Researchers observed loss of CDKN2A via several mechanisms — such as deletion, mutation, rearrangement with loss of function and methylation — in 72% of the samples.
“It is important to appreciate that squamous cell lung cancer is a very complex disease, with genomes profoundly altered by years of hydrocarbon exposure,” Govindan said during a press conference. “Alteration of CDKN2A is significant in this disease and should be examined in terms of therapy. Existing therapies should be studied in terms of squamous cell lung cancer patients because potential therapeutic targets for clinical trials with currently available drugs were identified in three-fourths of the study sample.
“This does not necessarily mean a drug that is currently inhibiting FGFR kinase would work in squamous cell lung cancer,” Govindan said. “This would require more examination in future clinical trials.”
For more information:
Govindan R. Abstract #7006. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: Dr. Govindan reported consultant/advisory positions with Bayer, Boehringer Ingelheim and Merck Serono.