Molecular Characteristics Determine Subtypes of Small Cell Lung Cancer

Qian Wang, MD, MPH, assistant professor at Case Western Reserve University, thoracic oncologist at University Hospital Seidman Cancer Center, discusses the progress of research into the molecular pathways responsible for developing small cell lung cancer (SCLC).

According to Wang, researchers identify 2 tumor suppressor genes that are missing in 90% of SCLC tumors: retinoblastoma 1 and TP53. There are other common gene changes known to occur in SCLC, including the Notch signaling gene family and MYC gene family, as well as epigenetic changes in CREBBP and EP300 genes.

Molecular subclassifications of SCLC have changed over time; these include SCLC type A, known for high RNA expression of ASCL1; type N, with high expression of NEUROD1; type P, with expression of POU2F3; and type Y, in which the transcriptional regulator YAP1 is highly expressed. Wang says this last type is controversial, as YAP1 expression may not represent a distinct subtype of tumors.

Another recently identified subtype, SCLC-I, is based on an inflamed gene signature and high expression of multiple immune genes. Studies have shown that patients with this subtype are more likely to respond well to immunotherapy, making it valuable to understanding which patients will respond to treatment.

TRANSCRIPTION:

0:08 | We know that SCLC is known for a loss of 2 tumor suppressor genes. One is called Rb1 or retinoblastoma 1, and the other one is called TP53. About 90% of SCLC cases have loss of those 2 genes. There are also other gene changes that have been found in SCLC, including the Notch gene family, MYC gene family and some epigenetic-related gene changes, such as CREBBP and EP300.

0:45 | In terms of its molecular subclassification, we're knowing more and more [and] recently, there are many studies looking at this, and we now know that SCLC is not just 1 entity. There are different subtypes based on its gene expression and molecular markers. So far, there are several of them. There are SCLC type A, [which is] it's known for expression of the ASCL1 gene, type N, type P, and Y as in the YAP1 gene. This one is probably a little bit controversial. Most recently, studies have shown there is another subtype called SCLC-I, indicated for ‘inflamed’, and recent studies showed that those SCLC-I type are more likely [to] have a better response to immunotherapy. This is a rapidly evolving field, so we're [learning] more about this.