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. 2015 Nov;17(11):817-25.
doi: 10.1016/j.neo.2015.11.002.

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome

Jill M Siegfried  1 , Yan Lin  2 , Brenda Diergaarde  3 , Hui-Min Lin  4 , Sanja Dacic  5 , Arjun Pennathur  6 , Joel L Weissfeld  3 , Marjorie Romkes  7 , Tomoko Nukui  8 , Laura P Stabile  9
Affiliations

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome

Jill M Siegfried et al. Neoplasia. 2015 Nov.

Abstract

Non-small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma.

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Figures

Supplemental Figure 1
Supplemental Figure 1
IPA network described by the seven-gene model. Red: Gene is overexpressed in cases with poor survival. Green: Gene is underexpressed in cases with poor survival.
Supplemental Figure 2
Supplemental Figure 2
log mRNA expression level versus IHC protein expression score in the subset of cohort 1 shown in Table 4 (43 cases) for CCNE1 (P = .001), MYC (P = .0003), and HER2 (P = .15).
Figure 1
Figure 1
Kaplan-Meier survival curves of NSCLC cases dichotomized using PCA of PAM50 genes. (A) DFS of ERβ-positive subset from cohort 1 (stage I NSCLC) using all 50 PAM50 genes (N = 35). (B) DFS of ERβ-positive subset from cohort 1 (stage I NSCLC) using the seven-gene model (N = 35). (C) PFS of ERβ-positive subset from cohort 2 (all-stage NSCLC) using all 50 PAM50 genes (N = 63). (D) PFS of ERβ-positive subset from cohort 2 (all-stage NSCLC) using the seven-gene model (N = 63).
Figure 2
Figure 2
Kaplan-Meier survival curves cases in TCGA cohorts dichotomized using PCA of PAM50 genes. (A) OS in the model using all 50 PAM50 genes in all stages of adenocarcinoma (N = 203). (B) OS in the model using all 50 PAM50 genes in stage I adenocarcinoma only (N = 101). (C) OS in the model using all 50 PAM50 genes in all squamous cell carcinoma cases (N = 220). (D) OS using the seven-gene model in all squamous cell carcinoma cases (N = 220).
See this image and copyright information in PMC

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