Abstract 3902: Comparison of allelic profiles of EGFR-mutated and ALK-translocated female adenocarcinomas of the lung by CGH microarrays: Implications for two distinct carcinogenesis pathways in non-smokers
Authors: Ninomiya Hironori , Takeuchi Kengo , Kato Motohiro , Okumura Sakae , Fujiwara Mutsunori , Ogawa Seishi , Ishikawa Yuichi 
Published: June 2012

Background: Adenocarcinoma is the most common form of lung cancer worldwide. In Japan, female adenocarcinomas are increasing, and more than two-thirds of them are non-smokers. EGFR mutation and EML4-ALK fusion, both of which are important for choice of molecular-targeted therapies, have been reported to be mutually exclusive. However, both genetic changes tend to occur in the similar populations, i.e; younger, non-smoking subjects. To examine the global allelic profiles to pursue specific genes for both the groups, SNP-chip-based high-resolution molecular allelo-karyotyping analysis was performed.

Methods: 51 female cases, 31 with EGFR mutation and 20 with EML4-ALK translocation, were enrolled in this study. All tumors were surgically resected at the Cancer Institute Hospital, Tokyo. Clinicopathological parameters including, age, pathological stage, differentiation grade of the tumor, tumor size were examined and microscopic lymphatic- and blood-vessel invasions were described. DNA was extracted from snap-frozen specimen. They were analyzed using Affymetrix GeneChip and our robust algorithm, CNAG/AsCNAR, to perform sensitive analysis of copy number alteration and allelic composition.

Results: EGFR mutation and EML4-ALK fusion were mutually exclusive. Tumors with EML4-ALK fusion conferred less-differentiated histology and smaller tumor size (P&lt;0.0001, P=0.0017, respectively). No statistical differences were found in age, pathological stage, and microscopic lymphatic/blood vessel invasions. With SNP-chip allelo-karyotyping analysis, among selected 23 amplified and 5 deleted regions, EML4-ALK tumors had significantly lower frequencies of allelic changes than EGFR tumors. For amplification, there were four regions (7p11.2, 16p13.3, 17q12, and 17q25.1) detected more frequently in EGFR tumors than in EML4-ALK tumors, and no regions found more in tumor with EGFR mutations than in those with EML-ALK translocation. For deletion, one region (9p24.1-p23) was again more often deleted in EGFR-mutated than in ALK-translocated tumors. Homozygous deletion was detected only at 9p21.3, including CDKN2A/p16, found in both groups.

Conclusions: Allelo-karyotyping analysis using high-resolution array technology revealed that EGFR-mutated tumors had more frequent amplifcations and deletions than ALK-translocated tumors at the particular 5 regions. Among them, 7p11.2 harbors EGFR, 17q12 contains ERBB2, and 9p24.1-p23 includes PTPRD. This study clearly demonstrated that gene dosage alterations were less prevalent in tumors with ALK fusion than those with EGFR mutations, implying two distinct carcinogenesis pathways in non-smokers’ lung cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2011-3902