ALK and ROS1 Lung Cancer Oncogenes May Also Drive Colorectal Cancer

Dara Aisner, MD, PhD

Gene rearrangements ALK and ROS1 that are known to drive subsets of lung cancer are also present in colorectal cancer according to a recent study in Molecular Cancer Research. It is now hoped that the drugs targeting ALK and ROS1 can also be applied to treat patients with colorectal cancer (CRC).

Dara Aisner, MD, PhD, an investigator at the Colorado University (CU) Cancer Center and a molecular pathologist at the CU School of Medicine, and colleagues used fluorescence in situ hybridization (FISH) to test for the oncogenic gene arrangements in 236 tumor samples. Samples were collected from patients who had previously been studied as part of a clinical trial in Australia that looked at a particular chemotherapy combination in metastatic colon cancer and had histologically confirmed colorectal adenocarcinoma. From each patient, three tumor tissue cores were taken and distributed in 10 blocks, making up a 12x8 grid of cores on each slide. Thirtynine of the patients were sampled twice, and three were sampled three times for quality control.

Two cases (0.8%) showed FISH patterns that were consistent with ROS1 rearrangement, specifically single 3’ROS1 signals. One case (0.4%) exhibited a pattern consistent with ALK rearrangement and also had predominantly single 3’ALK signals. Seven cases (3%) showed the atypical pattern 3’ALK doublets (3’/5’/3’ALK) associated with the C2orf44-ALK fusion. Signal variants for both ALK and ROS1 were also identified, including 25 cases with 3’/5’ fusion ALK doublets (10.6%), and 12 cases each (5.1%) with 3’ROS1 doublets (3’/5’/3’ROS1) and 3’/5’ fusion doublets for ROS1.

According to the study report, the researchers were surprised to find marked intratumoral heterogeneity for both KRAS mutation and ALK rearrangement status. Finding all four combinations of KRAS and ALK status throughout the specimen was especially unexpected, as was the identification of a region of high-grade dysplasia harboring both molecular alterations. Several other studies have shown that the KRAS mutation is an early event in colorectal carcinoma tumorigenesis.

“This is one of man y evolving studies demonstrating that while well described molecular alterations might be more common in a par ticular tumor type, to assume that they are exclusive to a single tumor type underestimates the diversity of biology,” Aisner explained in an interview with Oncology & Biotech News. “It is r eally only through sampling relatively large numbers of cases that we can f ind rare events, and in my mind, this further suggests that largescale evaluation for genomic alterations is an important part of the future of both scientific study and medicine. For colorectal carcinoma specifically, this identifies a rare but potentially targetable alteration that could provide treatment benefit for patients.”

Aisner said the researchers’ ultimate goal with this study is “to identify new targets for therapy for CRC patients, as well as patients with other tumor types.”

Aisner DL, Nguyen TT, Paskulin DD, et al. ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers [published online ahead of print December 2, 2013]. Mol Cancer Res. doi:10.1158/1541-7786.MCR-13-0479-T.