RUNX1T1 Amplification Induces "Small Cell" Cancer
Abstract
Small cell lung cancer (SCLC) is one of the most deadly cancers encountered by oncologists, with 5-year survival rates of less than 2% for patients with metastatic disease. Current thinking is that SCLC arises from a small population of specific neuroendocrine-like cells in the lung and is driven principally by concurrent mutation of two genes, TP53 and RB1. While this may be true for the majority of "everyday" SCLC patients, there are two other clinically important subgroups of cancer patients with "small cell" disease: so-called combined small cell lung cancer and extra-pulmonary small cell cancer. In combined SCLC, the tumors consist of both a SCLC component and a second subtype of lung cancer, such as adenocarcinoma, and it is believed that the second, more differentiated component has transformed into a small cell cancer. Similarly, extra-pulmonary small cell tumors have primary tumors that arise outside the lung, such as in the prostate or gastrointestinal tract, and transform into a small cell cancer. So in reality the term "small cell" simply describes a microscopic appearance, or phenotype. Clinically, however, this "small cell" phenotype is of great importance because it is treated the same, regardless of whether it is pulmonary, combined, or extra-pulmonary and predicts the same aggressive disease course with high mortality. Here we seek to validate one potential pathway leading to the formation of a "small cell" phenotype: through amplification of a gene called RUNX1T1, which we observed only in the "small cell" component of two combined SCLC tumors. We will do this by investigating more combined SCLC tumors for RUNX1T1 amplification, as well as by overexpressing RUNX1T1 in various cancer cell lines to see if it transforms them into a "small cell" phenotype. These studies may provide new ideas for treating SCLC itself, as well as other "small cell" cancer subtypes outside the lung, such as some prostate cancers, which have broad military relevance beyond smoking-related diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610568
Entities
People
- Afshin Dowlati
Organizations
- Case Western Reserve University
- United States Army