Comprehensive analysis of RET and ROS1 rearrangement in lung adenocarcinoma

Abstract

The success of crizotinib in ALK-positive patients has elicited efforts to find new oncogenic fusions in lung cancer. These efforts have led to the discovery of novel oncogenic fusion genes such as ROS1 and RET. However, the molecular and clinicopathologic characteristics associated with RET or ROS1 fusion, compared with ALK fusion-positive lung cancer, remain unclear. We accordingly analyzed the clinicopathologic characteristics of RET-and ROS1-fusion-positive lung adenocarcinomas. We further performed immunohistochemistry and fluorescence in situ hybridization analysis (FISH) in 15 cases of RET and 9 cases of ROS1 fusion tumors by identified NanoString's nCounter screening. RET fusion-positive patients were younger in age, never-smokers, and in early T stage; ROS1 fusion-positive patients had a higher number of never-smokers compared with patients with quintuple-negative (EGFR À /KRAS À /ALK À /ROS1 À /RET À ) lung adenocarcinoma. Histologically, RET and ROS1 fusion tumors share the solid signet-ring cell and mucinous cribriform pattern, as previously mentioned in the histology of ALK fusion tumors. Therefore, it can be presumed that fusion gene-associated lung adenocarcinomas share similar histologic features. In immunohistochemistry, the majority of 15 RET and 9 ROS1 fusion-positive cases showed positivity of more than moderate intensity and cytoplasmic staining for RET and ROS1 proteins, respectively. In FISH, the majority of RET and ROS1 rearrangement showed two signal patterns such as one fusion signal and two separated green and orange signals (1F1G1O) and an isolated 3 0 green signal pattern (1F1G). Our study has provided not only characteristics of fusion gene-associated histologic features but also a proposal for a future screening strategy that will enable clinicians to select cases needed to be checked for ROS1 and RET rearrangements based on clinicohistologic features.

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…This statement is evidence based and supported by 3 studies, 37,62,63 consisting of 1 PCS 62 and 2 RCSs. 37,63 All included studies were assessed for quality and none were found to have methodologic flaws that would raise concerns about the studies' findings (SDC Table 12). Refer to SDC Table 13 for a summary of findings from studies supporting the use of RET molecular testing.…”

“…30,37 However, this association has not been consistently observed across studies. 34 Other clinical characteristics, such as younger age, female sex, and non-Asian ethnicity, have been associated with ROS1 rearrangement in isolated studies only.…”

“…This recommendation is evidence based and supported by 9 studies, 30e38 6 of which informed on the association between ROS1 rearrangement and patient or tumor characteristics 30,31,34e37 and consisted of 1 prospective cohort study (PCS), 35 1 prospective-retrospective cohort study (PRCS), 31 and 4 retrospective cohort studies (RCSs). 30,34,36,37 The 3 remaining studies assessed clinical outcomes of patients treated with the ROS1-targeted therapy crizotinib 32,33,38 and included 1 nonrandomized clinical trial 33 and 3 RCSs. 32,38 All included studies were assessed for quality and none were found to have methodologic flaws that would raise concerns about the studies' findings (SDC Table 6).…”

“…62,64,65 RET fusion occurs more frequently in never smokers than ever smokers. 37,62,64,66,72 Patients with RET fusion harboring tumors are usually younger than patients with an EGFR mutation and have an equal gender distribution. 67 RET fusion proteins have been detected in adenocarcinoma 37,62,64 and in adenosquamous carcinoma.…”

“…37,62,64,66,72 Patients with RET fusion harboring tumors are usually younger than patients with an EGFR mutation and have an equal gender distribution. 67 RET fusion proteins have been detected in adenocarcinoma 37,62,64 and in adenosquamous carcinoma. 62 Histologic subtypes in adenocarcinomas include those with mucinous/signet ring cells and those with a cribriform 37,62,65 or solid growth pattern.…”