Chen Y et al. (2016), Distinct epithelial growth factor receptor muta...

ECB-ART-50008

Mol Clin Oncol 2016 May 01;45:749-755. doi: 10.3892/mco.2016.805.

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Distinct epithelial growth factor receptor mutation profile in non-small-cell lung cancer patients from the Xuanwei area of China.

Chen Y , Ye L , Stanford RR , Zhang D , Zhang X , Wei W .

Abstract
The Xuanwei county in China has a high incidence of lung cancer and related mortality. Previous studies have suggested that these cases may be associated with a distinctive pattern of mutations in the epithelial growth factor receptor (EGFR) gene. In this retrospective study, we investigated the mutation profile of EGFR in non-small-cell lung cancer (NSCLC) tissues from patients in Xuanwei, and the associated clinicopathological characteristics. Specimens from 258 consecutive patients with lung cancer (90 from Xuanwei and 168 from other areas of Yunnan province) were subjected to amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) to detect EGFR mutations. In 67 specimens from Xuanwei, the results were confirmed by direct DNA sequencing for EGFR mutations. Immunohistochemistry (IHC) for the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein was performed on all specimens from Xuanwei. We observed that Xuanwei patients presented with distinctive clinicopathological characteristics, including female gender predominance, younger age, higher rate of lymph node metastasis, higher rate of adenocarcinoma histological classification and lower disease stage, and a low rate of the 'classical' mutations on EGFR exons 19 and 21 compared with non-Xuanwei patients (7.8 and 21.6% vs. 49.3 and 39.7%, respectively; P<0.05 for combined data). However, a significantly higher percentage of Xuanwei patients harbored co-mutation of EGFR exons 18 and 20 compared with non-Xuanwei patients (45.1 vs. 4.1%, respectively; P<0.0001). Specimens from 2 Xuanwei patients (2.2%) were positive for the EML4-ALK fusion protein; by IHC, neither harbored EGFR mutations. There was no obvious association between EGFR mutations and disease stage or lymph node involvement. Thus, NSCLC patients in Xuanwei presented with a unique EGFR profile of high rates of co-mutation of exons 18 and 20, and low rates of exon 19 or 21 mutations when compared with patients from other areas in the same province, whereas only few of the tumors from Xuanwei patients expressed the EML4-ALK oncogene.

PubMed ID: 27123274
PMC ID: PMC4840835
Article link: Mol Clin Oncol

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References [+] :

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	Figure 1. Distribution of EGFR mutations. Exon 18+20 co-mutations (orange) were most common in the Xuanwei cohort, whereas in the non-Xuanwei cohort, mutations in exons 19 and 21, which are considered to be ‘classical’ mutations, were the most common, while mutations in exons 18, 20 and 18+20 occurred infrequently. EGFR, epidermal growth factor receptor.
	Figure 2. Immunohistochemistry for anaplastic lymphoma kinase (ALK). (A and C) A tumor sample with an iScore of 3 (see Materials and methods) was considered to be positive for ALK. (B and D) A sample with an iScore of 0 was considered to be negative for ALK. Magnification, ×100 for (A and B), ×200 for (C and D). Brown color, immunopositivity for ALK.
	Figure 3. Fluorescent in situ hybridization assay showing gene rearrangement in an (A) echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive and (B) EML4-ALK-negative carcinoma tissue. (A) ALK gene rearrangements are indicated by separated red and green signals (pair of arrows) labelled by two probes flanking the ALK breaking point in a single nucleus. (B) In normal nuclei, red and green fluorescent dots are colocalized or separated by less than two signal diameters apart (arrowheads).