Gene aberrations for precision medicine against lung adenocarcinoma

Abstract

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, is often triggered by an aberration in a driver oncogene in tumor cells. Examples of such aberrations are EGFR mutation and ALK fusion. Lung adenocarcinoma harboring such mutations can be treated with anticancer drugs that target the aberrant gene products. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such "druggable" driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in clinical trials. However, approximately 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. This review summarizes the current status of research on precision medicine against LADC and enumerates the research priorities for the near future.

Keywords: Chromatin remodeling genes; driver oncogene aberration; gene fusion; molecular targeting therapy; smoking.

Figure 1

Frequencies of driver oncogene aberrations in lung adenocarcinoma (LADC), shown as pie charts. Frequencies are shown for mutations in EGFR,KRAS,BRAF, and HER2 (driver mutations), fusions involving ALK,RET,ROS1,NRG1, and BRAF (driver fusions), and skipping of MET exon (ex) 14 (others). Data were obtained from a Japanese cohort (n = 319) from the National Cancer Center Hospital, Tokyo (NCC_Japan) and a US cohort (n = 230) from The Cancer Genome Atlas study (TCGA_USA).

Figure 2

Frequency of driver oncogene aberrations in lung adenocarcinoma (LADC) according to smoking status (a) and sex (b). Aberrations are shown for all Japanese and US cases for which information on sex and smoking was available. The oncogene aberrations referred to in the text are emphasized by exploding pie charts. ex, exon.

Figure 3

Molecular process of oncogene fusion. ALK,RET, and ROS1 oncogene fusions are the results of illegitimate DNA end‐joining repair of DNA strand breaks at defined genomic regions. Locations of breakpoints are indicated by yellow (lung adenocarcinoma) and gray (Chernobyl accident‐induced papillary thyroid cancers) arrowheads.22, 23 Breakpoints in lung adenocarcinomas of ever‐smokers are indicated by asterisks. Ch, chromosome.

Figure 4

Frequency of driver oncogene aberrations in invasive mucinous lung adenocarcinoma (IMA). Data were obtained from a Japanese cohort (n = 90) from the National Cancer Center Hospital, Tokyo (NCC_Japan)46 and a US cohort (n = 9) from The Cancer Genome Atlas study (TCGA_USA).7 The oncogene aberrations referred to in the text are emphasized by exploding pie charts.

Figure 5

Deduced molecular pathway of carcinogenesis and progression of lung adenocarcinoma, according to driver oncogene aberration. The relative timing of mutations in TP53, switch/sucrose non‐fermenting (SWI/SNF) chromatin remodeling, and other cancer‐related genes is unknown.