Development of Lung Adenocarcinomas with Exclusive Dependence on Oncogene Fusions

Abstract

This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n ¼ 200) enriched in patients with fusions (n ¼ 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P < 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P < 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n ¼ 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs. Cancer Res; 75(11); 2264-71. Ó2015 AACR.

Advances in targeted therapy and immunotherapy for treatment of lung cancer

“…Patients of fusion-positive cases, including ALK, ROS1 and RET fusions, often include young female and/or never/light-smokers 21,22) . In addi- tion, fusion-positive cases show a distinct profile with smaller numbers of nonsynonymous mutations in cancerrelated genes than in other LADC cases 3) . This result reenforced that oncogenic fusion products are a primary target of cancer therapy.…”

“…Driver mutations in EGFR, KRAS, HER2, and BRAF, and driver fusions involving ALK, RET, and ROS1 were examined in 608 LADC patients who had undergone surgical resection at the National Cancer Center. This figure was modified from our previous report 3) .…”

“…In LADC, gene mutations of EGFR, KRAS, BRAF, and HER2, and gene rearrangements involving ALK, ROS1 and RET have been mutually exclusively detected 1,3) . Therefore, these genes are considered to be driver genes and their suppression is considered to inhibit LADC development and metastasis.…”

An Overview of Genetic Polymorphism and Lung Cancer Risk

“…The association for this variant was validated in one study of female lung cancer patients with no history of smoking in Asian populations [16]. BPTF protein is required for c-MYC transcriptional activity [38,39] and somatic alterations in BPTF have been detected in a small percentage of ADC tissue samples [2,30,39]. However, further studies are needed to determine whether BPTF is responsible for susceptibility to ADC.…”

“…Advanced cancer genome technologies can be used to detect alterations in oncogenes, such as EGFR, KRAS, BRAF, HER2/ERBB2, ALK, RET, and ROS1 [1,2]. Despite the development of moleculartargeted drugs for oncogenic mutations, there are few efficient therapies for the advanced stage of lung cancer.…”