David J. Kwiatkowski M.D., Ph.D.

This grant is being fully funded by the Thomas G. Labrecque Foundation, through the Joan’s Legacy Grant Program.

Lay Description

Tuberous sclerosis is a tumor predisposition syndrome that is due to mutations in the TSC1 and TSC2 genes. Tuberous sclerosis patients often develop benign tumors in their lungs. No one has looked carefully at involvement of these genes in lung cancer. We have made preliminary observations that indicate that 1) loss of Tsc1 accelerates development of lung cancer in a preclinical model; and 2) the TSC genes appear to be involved by genetic analysis in about 25% of human lung cancers. Here we propose to delineate the involvement of the TSC genes in lung cancer development in greater detail. These patients may derive unique benefit from inhibitors of mTORC1, such as rapamycin.

Scientific Abstract

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome, characterized by development of distinctive benign tumors (hamartomas) in multiple organ systems, and due to inactivating mutations in either TSC1 or TSC2. Multifocal micronodular pneumocyte hyperplasia is seen in up to 50% of adult TSC patients, with occurrence of multiple 3-10 mm nodules consisting of hyperplastic type II pneumocytes throughout the lung on CT scans. TSC1 and TSC2 LOH has also been seen in 41% and 29% of atypical adenomatous hyperplasia-associated lung adenocarcinomas from Japanese patients.

We have recently discovered two further lines of evidence that suggest that the TSC genes are involved in lung cancer development: 1) in a preclinical model, loss of Tsc1 is markedly synergistic with K-ras activating mutation in accelerating lung cancer development; 2) about 25% of lung cancer patients have evidence for LOH in either TSC1 or TSC2, and about 2% show evidence for biallelic loss.

Therefore, we propose to examine 84 lung cancer cell lines (the DFCI-84 cell line collection) in detail looking for evidence of genetic, epi-genetic, or other mechanisms of loss of function of these genes. Methods will include MLPA, LR-PCR, RT-PCR sequencing, and pathway signaling immunoblot analysis on cell lysates. We will then extend these analyses to human lung cancer specimens.