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. 2009 Nov 1;69(21):8341-8.
doi: 10.1158/0008-5472.CAN-09-2477. Epub 2009 Oct 13.

Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers

Lynette M Sholl  1 , Beow Y Yeap, A John Iafrate, Alison J Holmes-Tisch, Yi-Ping Chou, Ming-Tsang Wu, Yih-Gang Goan, Li Su, Elisa Benedettini, Jian Yu, Massimo Loda, Pasi A Jänne, David C Christiani, Lucian R Chirieac
Affiliations

Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers

Lynette M Sholl et al. Cancer Res. .

Abstract

In a subset of lung adenocarcinomas, the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. For this study, we selected 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, and low and high polysomy (100% versus 54%, P = 0.009). EGFR amplification occurred invariably on the mutated and not the wild-type allele (median mutated/wild-type ratios 14.0 versus 0.33, P = 0.003), was associated with solid histology (P = 0.008), and advanced clinical stage (P = 0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival, 16 versus 31 months, P = 0.01) and when adjusted for stage (P = 0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and show distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.

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Figures

Figure 1
Figure 1
EGFR mutation status, copy number abnormalities and EGFR protein expression in lung adenocarcinoma and relationship with the predominant histology. Each row is a lung cancer sample. Black rectangles represent the results of EGFR sequencing (EGFR Sequence) or a predominant pattern (Dominant Histology). EGFR expression was categorized on a scale from 0 (absent staining) to 3 (strong staining) and illustrated on a grey scale from white (score=0), light grey (score=1), dark grey (score=2), and black (score=3). BAC, bronchioloalveolar histology.
Figure 2
Figure 2
Comparison of the genetic alterations and pathologic characteristics among the lung adenocarcinomas according to the EGFR copy number categories. Lung adenocarcinomas with EGFR amplification have very distinct genetic profiles. Panel A. Prevalence of EGFR mutations in the studied adenocarcinomas. Some adenocarcinomas have a concomitant mutation in the EGFR gene (dotted bars). In the EGFR amplified cancers there is a significant difference in the mutation frequency of EGFR exon 19 deletions (P = 0.009) but not in other mutations. Panel B. Furthermore, in cancers with EGFR exon 19 deletions, there is an increase in both wildtype and mutated EGFR copies in low and high polysomy cases (mean deleted:wildtype ratios 1.14 and 1.21, respectively), whereas there is a preferential increase of the deleted allele in amplified cases (mean deleted:wildtype ratios 36.3). The y axis indicates the log10 ratio between deleted allele and the wildtype allele. Panel C. Proportion of solid histology in each carcinoma. Boxes represent the mean values and whiskers the standard error of the mean. Panel D. EGFR protein expression.
Figure 3
Figure 3
Heterogenous histology, EGFR copy number, and protein expression in a gene amplified lung adenocarcinoma. The top panel shows a tumor field containing acinar and solid subtypes of adenocarcinoma. The lower panels show hematoxylin and eosin stain (400X), EGFR CISH (600X), and EGFR protein expression by immunohistochemistry (IHC) (400X). Part (A) shows acinar histology with low polysomy by CISH and 1+ protein expression. Part B shows solid histology with gene amplification in the form of homogenous staining regions by CISH and 3+ protein expression.
Figure 4
Figure 4
Kaplan-Meier estimates of disease-free survival among patients with stage II-IV lung adenocarcinoma. The median disease-free survival time was significantly worse among patients with adenocarcinoma with EGFR amplification than it was among patients without amplification (16 v 31 months, P = 0.01).
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