Sex-based differences in CEACAM5 expression in lung cancer

Abstract

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is expressed in 20-25% of non-small cell lung cancer (NSCLC) and there is interest in CEACAM5 as a biomarker given its potential for blood-based detection and investigational study as a drug target. Increased expression of CEACAM5 has been observed in semi-solid lung adenocarcinoma lesions, which have an increased prevalence in women and never smokers. Given this association, sex-based differences in CEACAM5 were evaluated. The Cancer Genome Atlas (TCGA) data on CEACAM5 expression in NSCLC tumors (n=994) in women (n=398) and men (n=596) were analyzed for differences in expression of CEACAM5 based on sex and histologic subtypes of adenocarcinoma and for correlations with overall survival (OS). Among all stages of NSCLC, mean expression of CEACAM5 was 143.3 fragments per kilobase of transcript per million (FPKM) with differences observed between female and male patients (194.5 vs. 109.2 FPKM, P<0.0001) and between adenocarcinoma and squamous cell carcinoma (239.3 vs. 46.2 FPKM, P<0.0001). Differences persisted among combined sex and histology subgroups. High CEACAM5 was not predictive of survival in NSCLC or adenocarcinoma overall, but was associated with worse survival among stage I female patients with adenocarcinoma (5-year OS CEACAM5 high =33% vs. low =64%, log-rank P=0.008). Higher levels of CEACAM5 expression are observed in NSCLC tumors in female patients and adenocarcinoma histology. High CEACAM5 expression in lung adenocarcinoma is associated with worse survival among female patients. The biologic impact of sex on CEACAM5 as a biomarker warrants further study.

Keywords: Biomarkers; adenocarcinoma; carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5); lung cancer; sex-based differences.

Figure 1

CEACAM5 expression. CEACAM5 expression in NSCLC stratified by sex (A), histologic subtype (B) and combined sex and histology (C). CEACAM5 expression in NSCLC from female patients is significantly higher than male patients (P<0.0001) and significantly higher in LUAD types than LUSC (P<0.0001). ****, P<0.0001. CEACAM5, carcinoembryonic antigen-related cell adhesion molecule 5; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; FPKM, fragments per kilobase of transcript per million; NSCLC, non-small cell lung cancer.

Figure 2

CEACAM5 and survival. High CEACAM5 expression (>57 FPKM) is not associated with survival in NSCLC patients overall. However, in women with adenocarcinoma, high CEACAM5 is a marker of poor prognosis and is significantly associated with worse survival outcomes in stage I (log-rank P=0.008) and stage IA (log-rank P=0.004) lung adenocarcinoma. NSCLC, non-small cell lung cancer; CEACAM5, carcinoembryonic antigen-related cell adhesion molecule 5; FPKM, fragments per kilobase of transcript per million.

Figure 3

CEACAM5 correlation with lung cancer driver mutations. CEACAM5 expression was correlated with gene expression for common lung cancer driver mutations among lung adenocarcinoma tumors in TCGA. EGFR, KRAS, BRAF, MET, and ALK expression are shown with positively correlated genes (blue) and negatively correlated genes (red) without any significant expression correlations. CEACAM5, carcinoembryonic antigen-related cell adhesion molecule 5; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma virus oncogene; BRAF, v-raf murine sarcoma viral oncogene homolog; MET, MET proto-oncogene; ALK, anaplastic lymphoma kinase; TCGA, The Cancer Genome Atlas.