Spectrum of LKB1, EGFR, and KRAS mutations in chinese lung adenocarcinomas

Abstract

Introduction: Somatic LKB1 mutations are found in lung adenocarcinomas at different frequencies in Caucasian and East Asian (Japanese and Korean) populations. This study was designed to characterize the frequency of LKB1 mutations, their relationship to EGFR and KRAS mutations, and their associated clinicopathologic characteristics in Chinese patients.

Methods: Two hundred thirty-nine lung adenocarcinomas consecutively collected from October 2007 to July 2009 were dissected into 3 to 4 small (3 mm) pieces for histopathological analyses of tumor content. Genomic DNA and/or cDNA from 86 samples with more than 70% tumor content were used for sequencing of LKB1 (exons 1-9), EGFR (exons 18-21), and KRAS (exon 2). LKB1 germline mutation status was determined by sequencing of genomic DNA from matched histologically distant lung tissues that are histologically normal.

Results: 6.9% of lung adenocarcinomas harbored LKB1 somatic mutations. A total of 10.5% of patients had an LKB1 germline polymorphism, F354L. Interestingly, in two of these patients, tumors displayed loss of heterozygosity at this allele. EGFR kinase domain and KRAS mutations were found in 66.3% and 2.3% of Chinese lung adenocarcinomas, respectively. Concurrent LKB1 and EGFR somatic mutations were observed in one patient. Both KRAS-mutant tumors harbored LKB1 mutations.

Conclusions: These data provide important clinical and molecular characteristics of lung adenocarcinomas from Chinese patients.

FIGURE 1

Sequencing analysis of tumor sample from laser capture microdissection revealed a homozygous somatic mutation of LKB1. Sequencing results show that the laser capture dissected tumor sample harbored one homozygous LKB1 deletion mutation del50L_53D (upper part) in contrast to the wild-type LKB1 from histologically normal lung from distant area (lower part). The 12-bp deletion is illustrated in the sequencing result of normal lung sample.

FIGURE 2

Homozygous alteration of LKB1 F354L in two Chinese lung adenocarcinoma patients. Sequencing data showed that in patients 316 (A) and 370 (B), who carry a germline LKB1 F354L allele (red arrows), this allele was homozygous in their lung cancer samples. The weak signal of wild-type LKB1 in the lung tumor from patient 370 is likely due to the contaminating stromal cells.