Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas
Open accessAbstract
To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined the exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor-normal pairs. Recurrent alterations in lung SqCCs were more similar to those of other squamous carcinomas than to alterations in lung ADCs. New significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. New amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase-Ras-Raf pathway alterations had mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least five predicted neoepitopes. Although targeted therapies for lung ADC and SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.
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The ability to achieve deep and durable inhibition of KRAS-dependent signaling is dependent on the susceptibility of KRAS mutated tumor cells to feedback reactivation of KRAS and pathways that mediate KRASdependent signaling.
“The ability to achieve deep and durable inhibition of KRAS-dependent signaling is dependent on the susceptibility of KRAS mutated tumor cells to feedback reactivation of KRAS and pathways that mediate KRASdependent signaling[30, 31].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [30]
The Results section (‘Identifying Ras/Raf/RTK drivers in lung ADC’; page unavailable) describes pathway alterations and KRAS mutations, but not whether feedback reactivation affects deep or durable inhibition of KRAS-dependent signaling. Searches for ‘feedback reactivation’ and ‘deep and durable inhibition’ found no passage addressing that relationship. (LLM, conf=0.76)
Experimental — accuracy not yet measuredKRAS mutations account for about 78% of RAS mutations in NSCLC, and activating missense KRAS mutations occur in about 25% of NSCLCs, usually mutually exclusive with other actionable drivers such as EGFR, BRAF and ALK.
“KRAS mutations predominate in NSCLCs, accounting for ~78% of all RAS mutations found in such tumours17. The activating missense KRAS mutations that occur in ~25% of NSCLCs19–23 are typically mutually exclusive with other clinically actionable driver mutations, such as those in EGFR, BRAF and ALK24.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [24]
Large-scale profiling studies in NSCLC have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation.
“Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation15, 34, 58–62.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [61]
The genomic landscape of LUAD has been extensively characterized.
“Although the genomic landscape of LUAD has been extensively characterized (Campbell et al., 2016; Cancer Genome Atlas Research, 2014)”
From Commensal Microbiota Promote Lung Cancer Development via γδ T Cells (2019) · cites this paper as Campbell et al., 2016
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References 69 · Cited by 1,200
Research works printed but not linked: 2
- [1]Stewart BW Wild CP World Cancer Report 2014 2014 International Agency for Research on Cancer 39432694
- [48]Hoadley KA Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin Cell 2014 158 929 944 25109877 PMC4152462
- Authors
- Cancer Genome Atlas Research Network, Campbell, J. D., Alexandrov, A., Kim, J., Wala, J., Berger, A. H., Pedamallu, C. S., Shukla, S. A., Guo, G., Brooks, A. N., Murray, B. A., Imielinski, M., Hu, X., Ling, S., Akbani, R., Rosenberg, M., Cibulskis, C., Ramachandran, A., Collisson, E. A., Kwiatkowski, D. J., Lawrence, M. S., Weinstein, J. N., Verhaak, R. G. W., Wu, C. J., Hammerman, P. S., Cherniack, A. D., Getz, G., Artyomov, M. N., Schreiber, R., Govindan, R., & Meyerson, M.
- Affiliations
- Broad Institute (US)
- ITMO University (RU)
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Corresponding author
- Govindan, Ramaswamy
- Meyerson, Matthew
- ORCID
- Campbell, Joshua D
- Alexandrov, Anton
- Kim, Jaegil
- Wala, Jeremiah
- Berger, Alice H
- Pedamallu, Chandra Sekhar
- Shukla, Sachet A
- Guo, Guangwu
- Brooks, Angela N
- Imielinski, Marcin
- Hu, Xin
- Akbani, Rehan
- Rosenberg, Mara
- Cibulskis, Carrie
- Collisson, Eric A
- Kwiatkowski, David J
- Lawrence, Michael S
- Weinstein, John N
- Verhaak, Roel G W
- Wu, Catherine J
- Hammerman, Peter S
- Cherniack, Andrew D
- Getz, Gad
- Artyomov, Maxim N
- Schreiber, Robert
- Govindan, Ramaswamy
- Meyerson, Matthew
- Venue
- Nature Genetics
- Published
- 2016-05-09
- Volume
- 48
- Issue
- 6
- Pages
- 607-616
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4884143
- OpenAlex
- W2346025119
- Cited by
- 1,200
- References
- 69
- Citations by year
- 2026: 56 · 2025: 86 · 2024: 126 · 2023: 133 · 2022: 141 · 2021: 166 · 2020: 137 · 2019: 131 · 2018: 115 · 2017: 88 · 2016: 19
- FWCI
- 105.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Human Genome Research Institute (T32HG002295)
- National Cancer Institute (R01CA184922, U24CA126546, U24CA144025, U24CA199461, U24CA143883, U24CA143845, U24CA126544, K08CA163677, U24CA143867, U24CA143848, K99CA197762, P01CA120964, R01CA155010, P30CA016672, R35CA197568)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- lung adenocarcinoma, lung squamous cell carcinoma, somatic mutations, copy number alterations, neoantigens, driver mutations, RAS/RAF pathway, SOS1, Vav1, RASA1, MIR21, MAPK1, immunotherapy, tumor immunogenicity
- MeSH terms
- Adenocarcinoma, Antigens, Neoplasm, Carcinoma, Squamous Cell, Humans, Lung Neoplasms, Recurrence, Genome, Human, DNA Copy Number Variations
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