Abstract
Despite the urgency for prevention and treatment of lung adenocarcinoma (LUAD), we still do not know drivers in pathogenesis of the disease. Earlier work revealed that mice with knockout of the G-protein coupled receptor Gprc5a develop late onset lung tumors including LUADs. Here, we sought to further probe the impact of Gprc5a expression on LUAD pathogenesis. We first surveyed GPRC5A expression in human tissues and found that GPRC5A was markedly elevated in human normal lung relative to other normal tissues and was consistently downregulated in LUADs. In sharp contrast to wild-type littermates, Gprc5a–/– mice treated chronically with the nicotine-specific carcinogen NNK developed LUADs by 6 months following NNK exposure. Immunofluorescence analysis revealed that the LUADs exhibited abundant expression of surfactant protein C and lacked the clara cell marker Ccsp, suggesting that these LUADs originated from alveolar type II cells. Next, we sought to survey genome-wide alterations in the pathogenesis of Gprc5a–/– LUADs. Using whole exome sequencing, we found that carcinogen-induced LUADs exhibited markedly higher somatic mutation burdens relative to spontaneous tumors. All LUADs were found to harbor somatic mutations in the Kras oncogene (p. G12D or p. Q61R). In contrast to spontaneous lesions, carcinogen-induced Gprc5a–/– LUADs exhibited mutations (variants and copy number gains) in additional drivers (Atm, Kmt2d, Nf1, Trp53, Met, Ezh2). Our study underscores genomic alterations that represent early events in the development of Kras mutant LUAD following Gprc5a loss and tobacco carcinogen exposure and that may constitute targets for prevention and early treatment of this disease.
Original language | English |
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Pages (from-to) | 1589-1599 |
Number of pages | 11 |
Journal | International Journal of Cancer |
Volume | 141 |
Issue number | 8 |
DOIs | |
State | Published - Oct 15 2017 |
Bibliographical note
Publisher Copyright:© 2017 UICC
Funding
The tobacco carcinogen NNK with a purity of >99% was purchased from Midwest Research Institute (The National Cancer Institute's Chemical Carcinogen Reference Standard Repository).
Funders | Funder number |
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Midwest Research Institute - Kansas City | |
National Childhood Cancer Registry – National Cancer Institute | R01CA205608 |
National Childhood Cancer Registry – National Cancer Institute |
Keywords
- Gprc5a
- Kras
- carcinogenesis
- lung adenocarcinoma
- whole-exome sequencing
ASJC Scopus subject areas
- Oncology
- Cancer Research