Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients

Abstract

Purpose: Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.

Patients and methods: We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

Results: This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.

Conclusion: These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.

Fig 1.

Clinicopathologic characteristics and genetic aberrations across 104 lung squamous cell carcinomas. (A) Rate of synonymous and nonsynonymous mutations, expressed in mutations per megabase (Mb) of covered target sequence in association with clinical parameters for the samples. In the bottom panel, the first row indicates smoking status, the second row sex, and the third row cancer stage. (B) Heatmap representation of individual mutations present in 104 lung squamous cell carcinoma samples in association with information from (A). It displays the mutational types in a given sample and in a given gene in a two-dimensional matrix. (Left) Percentages of mutations, representing at least one mutational event in each gene. (Right) List of recurrently mutated genes. FGFR, RAS, SWI/SNF, NOTCH, and WNT mini-gene sets are shown as single tracks because there was complete exclusivity of mutations within these gene families. FGFR* indicates conglomerated representation of FGFR1 + FGFR3, RAS*: HRAS + NRAS + KRAS, SWI/SNF*: ARID1A + ARID1B + PBRM1, NOTCH*: NOTCH1 + NOTCH3, WNT*: APC + CTNNB1. (C) Somatic copy-number alterations (SCNAs) of samples in association with (A) and (B). Significant SCNAs are shown, highlighting the samples with threshold copy-number changes specified in the lower bottom panel. Indel, insertions and deletions.

Fig 2.

Recurrent FGFR3-TACC3 fusion identified in lung squamous cell carcinoma. (A) FGFR3-TACC3 fusion identified from RNA sequencing; 26 split-reads that span the FGFR3-TACC3 junction are shown. (B) Left: FGFR3-TACC3 fusion-specific polymerase chain reaction from complementary DNA derived from patients with lung squamous cell carcinoma. Right: sequencing chromatogram from two patient samples spanning the fusion junction. Shown in box are the translational reading frames and designation of amino acids. M, DNA marker. J1, patient identification number.

Fig 3.

Diagram of integrated lung squamous cell carcinoma pathways. Proposed diagram integrating five different core pathways of lung squamous cell carcinoma. Green, substitution mutations; black, truncating mutations; red, amplifications; blue, deletions.