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Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients
Youngwook Kim1, Peter S Hammerman, Jaegil Kim
1Youngwook Kim, Ji-ae Yoon, Yoomi Lee, Yeong Kyung Yoo, and Keunchil Park, Samsung Medical Center, Samsung Biomedical Research Institute; Jong-Mu Sun, Hong Kwan Kim, Yong Soo Choi, Kwhanmien Kim, Young Mog Shim, Yoon-La Choi, Jhingook Kim, Jin Seok Ahn, Myung-Ju Ahn, and Keunchil Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Sukki Cho, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seoul; In-Jae Oh, Kyu-Sik Kim, Sang-Yun Song, Kook-Ju Na, and Young-Chul Kim, Chonnam National University Hwasun Hospital, Jeonnam, Republic of Korea; Peter S. Hammerman, Jaegil Kim, Chandra Sekhar Pedamallu, Kristian Cibulskis, Michael S. Lawrence, Petar Stojanov, Scott L. Carter, Aaron McKenna, Chip Stewart, Andrey Y. Sivachenko, Gad Getz, and Matthew Meyerson, Broad Institute of Harvard and MIT, Cambridge; Matthew Meyerson, Harvard Medical School; Peter S. Hammerman and Chandra Sekhar Pedamallu, Dana-Farber Cancer Institute; Gad Getz, Massachusetts General Hospital Cancer Center, Boston, MA; and Matthew D. Wilkerson and D. Neil Hayes, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
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.
Insights
Genomic analysis of Korean lung squamous cell carcinoma (SCC) reveals a high mutation rate and common alterations in key genes. These findings pave the way for identifying new precision medicine targets for this prevalent cancer.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Lung squamous cell carcinoma (SCC) is a major cancer type lacking targeted therapies.
- Understanding the molecular drivers of lung SCC is crucial for developing effective treatments.
Purpose of the Study:
- To identify potential therapeutic targets in lung SCC.
- To analyze somatic genome alterations in Korean lung SCC patients.
- To compare genomic profiles with North American lung SCC cohorts.
Main Methods:
- Whole-exome sequencing of 104 Korean lung SCC tumors and matched normal DNA.
- Copy-number and transcriptome analysis on a subset of samples.
- Investigation of clinical associations with somatic alterations.
Main Results:
- Lung SCC cohort exhibits high mutational burden (average 261 somatic mutations/tumor) with a smoking-related mutational signature.
- Mutations were enriched in TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA.
- Korean and North American lung SCC samples showed similar genomic alteration spectra, unlike lung adenocarcinoma.
- Recurrent FGFR3-TACC3 fusion, a potential therapeutic target, was identified.
Conclusions:
- This study provides crucial insights into the genomic landscape of lung SCC.
- Identified genomic alterations represent potential targets for precision medicine.
- Findings address the unmet medical needs in lung SCC treatment.
