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Integrative genomics identifies SHPRH as a tumor suppressor gene in lung adenocarcinoma that regulates DNA damage
Amy L Nagelberg1,2, Tianna S Sihota1,2, Yu-Chi Chuang1,3
1Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
Background:
Identification of driver mutations and development of targeted therapies has considerably improved outcomes for lung cancer patients. However, significant limitations remain with the lack of identified drivers in a large subset of patients. Here, we aimed to assess the genomic landscape of lung adenocarcinomas (LUADs) from individuals without a history of tobacco use to reveal new genetic drivers of lung cancer.
Methods:
Integrative genomic analyses combining whole-exome sequencing, copy number, and mutational information for 83 LUAD tumors was performed and validated using external datasets to identify genetic variants with a predicted functional consequence and assess association with clinical outcomes. LUAD cell lines with alteration of identified candidates were used to functionally characterize tumor suppressive potential using a conditional expression system both in vitro and in vivo.
Results:
We identified 21 genes with evidence of positive selection, including 12 novel candidates that have yet to be characterized in LUAD. In particular, SNF2 Histone Linker PHD RING Helicase (SHPRH) was identified due to its frequency of biallelic disruption and location within the familial susceptibility locus on chromosome arm 6q. We found that low SHPRH mRNA expression is associated with poor survival outcomes in LUAD patients. Furthermore, we showed that re-expression of SHPRH in LUAD cell lines with inactivating alterations for SHPRH reduces their in vitro colony formation and tumor burden in vivo. Finally, we explored the biological pathways associated SHPRH inactivation and found an association with the tolerance of LUAD cells to DNA damage.
Conclusions:
These data suggest that SHPRH is a tumor suppressor gene in LUAD, whereby its expression is associated with more favorable patient outcomes, reduced tumor and mutational burden, and may serve as a predictor of response to DNA damage. Thus, further exploration into the role of SHPRH in LUAD development may make it a valuable biomarker for predicting LUAD risk and prognosis.
Insights
Researchers identified SHPRH as a tumor suppressor gene in lung adenocarcinoma (LUAD). Its inactivation is linked to poor outcomes and DNA damage tolerance, suggesting it could be a biomarker for LUAD risk and prognosis.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) outcomes have improved with targeted therapies, but many patients lack identified driver mutations.
- Non-smokers with LUAD represent a distinct group where novel genetic drivers are needed.
- Understanding the genomic landscape of LUAD in non-smokers is crucial for identifying new therapeutic targets.
Purpose of the Study:
- To identify novel genetic drivers in lung adenocarcinoma (LUAD) from individuals without a history of tobacco use.
- To characterize the functional role of identified candidate genes in LUAD development.
- To assess the potential of identified genes as biomarkers for LUAD prognosis and treatment response.
Main Methods:
- Integrative genomic analyses, including whole-exome sequencing and copy number analysis, were performed on 83 LUAD tumors.
- External datasets were used for validation of identified genetic variants and their association with clinical outcomes.
- Functional characterization of candidate genes, specifically SHPRH, was conducted in LUAD cell lines using in vitro and in vivo models.
Main Results:
- Twenty-one genes showed evidence of positive selection, with 12 novel candidates identified in LUAD.
- SNF2 Histone Linker PHD RING Helicase (SHPRH) was identified due to frequent biallelic disruption and its location on chromosome 6q.
- Low SHPRH mRNA expression correlated with poor survival, reduced tumor burden, and increased tolerance to DNA damage in LUAD patients.
Conclusions:
- SHPRH functions as a tumor suppressor gene in LUAD, with its expression linked to better patient outcomes.
- SHPRH inactivation is associated with increased tolerance to DNA damage, suggesting a role in DNA repair pathways.
- SHPRH may serve as a valuable biomarker for predicting LUAD risk, prognosis, and response to DNA-damaging therapies.
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