Accumulating evidence indicates the co-existence of classic oncogenes, involving EGFR, ALK, ROS1 and MET, has identified in lung adenocarcinoma patients, especially younger and women patients without smoking history. However, few studies have focused on the frequency of ROS1 rearrangement or co-alterations of EGFR, ROS1 and EML4-ALK in micropapillary lung adenocarcinoma (MPA) and non-micropapillary lung adenocarcinoma (LA). Therefore, we investigated the relationship between the most common oncogenic mutations and molecular characteristics in Chinese lung adenocarcinoma patients.
Like in previous reports[19, 20], we here discovered that MPA has higher rate of lymph node metastasis and earlier disease stage compared with LA (Table 1). Increasing studies demonstrated that MPA had a poorer prognosis compared with those without micropapillary component or other histological subtypes[21–27]. Our results further implied that the higher prevalence of lymph node metastasis may be a valuable poor prognosis marker for MPA.
An investigation of 15 MPAs revealed that the mutational status of EGFR, KRAS and BRAF harbored 73% mutually exclusive mutations in the Western population[28]. A study involving 21 micropapillary predominant lung adenocarcinoma patients showed that oncogenic mutations in EGFR, HER2 and RET were apparently frequent in 95.2% Chinese people[12]. Here, our results manifested the majority (47 out of 55, 85.5%) of MPA harbored the driver genetic alterations of EGFR (76.4%), ROS1 (10.9%), or EML4-ALK (5.5%) from a Chinese cohort. The previous cohort detected no ROS1 fusions[12], but two other independent teams found ROS1 rearrangements in MPA[13, 14]. Therefore, there is no consistent conclusions about ROS1 rearrangements in MPA patients. Here, our cohort reported that 6 MPA cases possessed ROS1 rearrangements. In the past, oncogenic mutations involving EGFR, KRAS, ALK, RET, ROS1 and MET were regarded as mutually independent events. However, two or more cancer-associated genes were recently found in lung adenocarcinoma cases. For example, several teams identified the concurrence of EGFR mutation with ALK or ROS1 fusions or others oncogenic drivers in non-small cell lung cancer, and the patients showed distinctive clinical responses to TKIs[29–32]. Therefore, these reports demonstrated the coexistent alterations of two or more drivers in lung adenocarcinoma cases and the affected patients may select appropriate therapy strategy according to the complex genetic alteration. Our study indicated that 7.3% MPA cases harbored two-driver alterations of EGFR, ROS1 or EML4-ALK, while only one LA case (1.3%) had double driver mutations. These results declare that MPA has higher prevalence of oncogenic mutations in comparison with LA.
So far, there is little progress on digging the pathogenic mechanism of MPA or the treatment of this subtype by TKIs. Therefore, based on our finding, we will focus on elucidating the function on ROS1 rearrangement and EGFR mutations in MPA by establishing the cell and animal models both in vitro and in vivo. In addition, we will test the efficacy of one targeted TKI or combined TKIs for MPA, and provide the potential treatment strategy.
In summary, we report for the first time the relationship between the most common oncogenic mutations and pathology characteristics in Chinese lung adenocarcinoma patients. We also discover the higher incidence of ROS1 rearrangements and the coexistence of genetic alterations involving EGFR, ROS1 and EML4-ALK in MPA cases, indicating that targeting of ROS1 rearrangements and/or EGFR mutations may provide a novel strategy and potential prognosis marker for these patients. However, these results still should be confirmed by further studies with larger cases and more clinical information, especially prognosis data and mechanism.