Researchers Identify Genetic Mutations Associated with Poor Outcomes in Lung Cancer Patients

New studies are suggesting that there are novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy in patients with lung cancer.

Investigators at Moffitt Cancer Center have found that STK11 gene mutations are associated with changes in immune surveillance genes, while TP53 mutations are associated with changes in proliferation genes.

There are four gene mutations (KRAS, TP53, STK11, and EGFR) that most commonly occur in lung cancer.  However, there are limited effective therapies to target these mutations. The researchers hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors.

They analyzed gene expression patterns in 442 lung adenocarcinomas and screened the tumors for gene mutations known to contribute to lung cancer development. They used this data to assess associations between genetic alterations, gene expression patterns, and clinical outcomes.

They found that 34.8% of lung tumors had KRAS mutations, 10.6% had mutations in EGFR, 15.3% in STK11, and 25.1% in TP53. Lung cancer patients who had KRAS mutations had a shorter survival than patients without KRAS mutations. They found that lung cancer patients who had EGFR mutations had a better overall survival (OS) than patients without EGFR mutations.

The study also revealed that tumors with either TP53 or STK11 mutations had different gene expression patterns. Lung tumors with TP53 mutations had higher levels of genes that are associated with proliferation and growth, while lung tumors with STK11 mutations had lower levels of genes that are associated with immune surveillance. They confirmed these results by showing that tumors with STK11 mutations had reduced levels of T cells.

“These findings could impact therapeutic treatments. Tumors can develop mechanisms to avoid immune detection, thereby allowing continued tumor growth,” said Matthew Schabath, PhD, assistant member of the Cancer Epidemiology Program at Moffitt Cancer Center, Tampa, Fla., in a press release.   

Dr. Schabath said currently patients with lung cancer have a 5-year survival rate of only 16%, and so there remains an urgent need to identify new genetic-based targets for precision-based medicine strategies. The new data from this investigation suggests that lung tumors with STK11 mutations may be less responsive to these drugs.

“These studies reveal a novel link between common gene mutations and tumor immune surveillance. Therefore, gene mutations may also impact the response to immunotherapeutic agents, and targeting pathways controlled by these mutations could provide new opportunities for enhancing the immunotherapy response in patients,” said Amer Beg, PhD, who is a senior member of the Immunology Program at Moffitt.

The study was published online in the October 19, 2015, issue of Oncogene and is one of the largest studies of its kind. All data from the study was publically released to provide a new and valuable resource for cancer researchers worldwide. 

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