Moffitt Cancer Center study finds link between common gene mutations and tumor immune surveillance

Moffitt Cancer CenterNov 12 2015

Learning if a lung cancer patient has genetic mutations can help oncologists determine the best approach to treatment. 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. With this in mind, Moffitt Cancer Center performed an extensive genetic analysis of lung cancer specimens to unravel how mutations in the two of those genes (TP53 and STK11) contribute to the biology of lung cancer and patient outcomes.

Patients with lung cancer have a 5-year survival rate of only 16 percent. "Given the low survival rates among lung cancer patients, there remains an urgent need to identify new genetic-based targets for precision-based medicine strategies, such as immune therapy." explained Matthew B. Schabath, Ph.D., assistant member of the Cancer Epidemiology Program at Moffitt

The researchers 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. This is one of the largest studies of its kind and all data from the study was publically released to provide a new and valuable resource for cancer researchers worldwide.

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

Importantly, the researchers discovered 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 immune cells or T cells.

"These findings could impact therapeutic treatments. Tumors can develop mechanisms to avoid immune detection, thereby allowing continued tumor growth," said Schabath. Several agents currently in clinical development function by restimulating the immune system to target the tumor. The data from the Moffitt researchers 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 A. Beg, Ph.D., senior member of the Immunology Program at Moffitt.