Prognostic implications of EGFR protein expression in sporadic colorectal tumors: Correlation with copy number status, mRNA levels and miRNA regulation

Sofía Del Carmen,Mar Abad,Ruth Gervas,Jacinto García,José María Sayagués,Oscar Bengoechea,Luís Antonio Corchete,José Antonio Álcazar,María Garcia,Alba Rodriguez,Luis Muñoz-Bellvis

doi:10.1038/s41598-020-61688-7

Abstract

Sporadic colorectal cancer (sCRC) is the third most frequent cancer worldwide and the second most common cause of cancer-related deaths (mainly due metastatic dissemination). We investigated the immunohistochemical expression of frequently altered proteins in primary tumors from 51 patients (25 liver metastatic and 26 non-metastatic cases) with a median 103 months follow-up (103 months). We evaluated EGFR copy number (using SNP arrays and FISH) and its expression and regulation (by mRNA and miRNA arrays). We found differences between metastatic and non-metastatic sCRCs for MLH1 (p = 0.05), PMS2 (p = 0.02), CEA (p < 0.001) and EGFR (p < 0.001) expression. EGFR expression was associated with lymph node metastases (p = 0.001), liver metastases at diagnosis (p < 0.001), and advanced stage (p < 0.001). There were associations between EGFR expression-, EGFR gene copy number- and EGFR mRNA levels. We found potential interactions of two miRNAs targeting EGFR expression, (miR-134 and miR-4328, in non-metastatic and metastatic tumors, respectively). EGFR expression was associated with a worse outcome (p = 0.005). Multivariate analysis of prognostic factors for overall survival identified that, the expression of EGFR expression (p = 0.047) and pTNM stage (p < 0.001) predicted an adverse outcome. EGFR expression could be regulated by amplification or polysomies (in metastatic tumors), or miRNAs (miRNA-134, in non-metastatic tumors). EGFR expression in sCRC appears to be related to metastases and poor outcome.

Highlights

Sporadic colorectal cancer is the third most common cancer diagnosed worldwide and the second most frequent cause of cancer-related mortality[1,2]
The only statistically significant differences identified between liver metastatic and non-metastatic Sporadic colorectal cancer (sCRC) were those involving antibodies MLH1 (p = 0.05), PMS2 (p = 0.02), carcinoembryonic antigen (CEA) (p < 0.001) and EGFR (p < 0.001)
Sporadic colorectal cancer patients who do not exhibit or develop distant metastasis can often be cured by surgical resection of the primary tumor, and the optional administration of adjuvant therapy

Summary

Introduction

Sporadic colorectal cancer (sCRC) is the third most common cancer diagnosed worldwide and the second most frequent cause of cancer-related mortality[1,2]. We and others researchers have demonstrated that metastatic sCRC-specific genomic alterations, e.g., del(17p) and del(22q), are common to primary tumors and their paired liver metastatic samples[5,6,7,8], but are absent from non-metastatic sCRC tumors[6]. Despite the exceptional utility of genomic methods in the discovery phase of experimentation, their use is limited in most hospitals because they are expensive techniques and difficult to apply in paraffin-embedded material For these reasons, in practice, most routine diagnoses are performed using immunohistochemistry (IHC) techniques. We used IHC techniques to investigate the prognostic value of the expression of the proteins most commonly altered in the primary colorectal carcinomas of 51 sCRC patients (25 liver metastatic and 26 non-metastatic cases) with a long median follow-up. Our study revealed that EGFR protein expression and copy number are closely related and that EGFR expression, as shown by IHC, is an independent prognostic factor of overall survival (OS) in sCRC patients

Methods

Results

Conclusion