Abstract IA5: Genetic and genomic difference in lung cancer based on ethnicity
Authors: Mitsudomi Tetsuya , Suda Kenichi , Tomizawa Kenji , Yatabe Yasushi , Matsuo Keitaro 
Published: March 2013

Abstract
Since the discovery of somatic mutation of the gene for the epidermal growth factor receptor (EGFR) in the non-small cell lung cancer (NSCLC), it has been known that EGFR mutation tends to occur in a certain subset of patients with a distinct clinical-pathologic feature. Namely, EGFR mutations are predominantly found in female, non-smoking patients with adenocarcinoma of East Asian origin. According to the data of 2880 patients complied from the literature, EGFR mutations are highly dependent on ethnicity (East Asians, 32% compared with Caucasians, 7%), sex (male, 10% compared with female, 38%), smoking history (never smoked, 47% compared with smoked, 7%), and histologic type (adenocarcinoma, 30% compared with other types of lung cancer, 2%) (1). In contrast, KRAS mutations predominantly occur in Caucasian patients with smoke exposure. KRAS mutation is present ∼30% of adenocarcinoma of Caucasian patients, while it is present in ∼10% of Asian patients (2). There appears to be no ethnic difference for incidence of ALK gene translocation although it is more frequent in non-smoking population similar to EGFR mutation.
According to Shigematsu and Gazdar, incidence of EGFR mutations is significantly different between East Asian patients (33%) and non-Asian patients (6%) (P &lt; 0.001) in their analysis of 2,347 cases (3). When limited to adenocarcinoma, this difference is also present (48% vs. 12%). They also reported that 4 of 5 Asian patients with lung cancer in the United States and Australia had EGFR mutations, suggesting that genetics may be more important than geographic factors for affecting EGFR mutations (3).
The remarkable difference in prevalence of EGFR mutation in NSCLC patients between East Asian and Western population suggests that there may be differences in background risk/protective factors between these two populations.
Several polymorphic variations in EGFR gene including a CA repeat in intron 1 (CA simple sequence repeat 1 (CA-SSR1) (lower number of repeats) or single nucleotide polymorphisms in the promoter region (-216(G/T or T/T) and -191 (C/A or A/A) have been identified. All these polymorphisms are associated with increased expression of the EGFR protein and are less frequent in East Asians (4). Therefore, East Asians in general make less EGFR protein. To make lung cancer to occur, EGFR gene should be mutated and amplified because mutation of the EGFR gene is a prerequisite for amplification, if a certain amount of mutated EGFR protein is necessary to activate EGFR pathway signaling. This may partly explain ethnic difference in incidence of EGFR gene mutation described above (4).
We are now conducting Genome-Wide Association Study in Japanese to identify genetic locus associated with the risk of EGFR mutated and non-mutated NSCLC. In a part of the phase I study at Aichi Cancer Center [341 lung cancer cases (125 EGFR mutated and 216 EGFR wild-type) and 972 non-cancer controls] using Illumina platform-based genome scanning data, we have identified two loci showing genome-wide significance (p&lt;10−8) and two loci suggestive significance (10−8∼−5) loci for the risk of EGFR mutation. For EGFR wild-type NSCLC, three loci showed genome-wide significance and four loci showed suggestive significance. Some of the loci partly explain difference in the prevalence of EGFR mutation. A risk-allele frequency of one of the loci showing association with EGFR mutated NSCLC was high in HapMap JPT (0.972) and low in HapMap CEU (0.438). We are now validating our finding in other Japanese cohorts. We believe that difference in EGFR mutation among NSCLC patients between East Asian and Western population can be explained by genetic difference.