The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases stimulates a number of signal transduction cascades (e.g., Ras/Raf/MEK/ERK, PI3K/AKT) that regulate diverse cellular processes, such as proliferation, differentiation, survival, migration and adhesion.³ These signaling pathways are important in normal cellular homeostasis, but aberrant activation of the EGFR members are crucial in esophageal carcinogenesis. This family of receptors comprises EGFR (also referred to as erbB1), erbB2, erbB3, and erbB4. The receptors have the ability to homo- or heterodimerize on engagement with one of several ligands: TGF (transforming growth factor)-α, EGF (epidermal growth factor), amphiregulin, heparinbinding EGF-like growth factor, betacellulin, and epiregulin. Tyrosine phosphorylation of homo- or heterodimers of EGFRs creates docking sites for
signaling proteins or adapter proteins. EGFR is commonly overexpressed in early-stage esophageal cancer, and overexpression correlates with a poor prognosis.⁴,⁵,⁶,⁷ EGFR overexpression is typically due to increased engagement with ligands and decreased turnover. However, mutation of a tyrosine residue in the cytoplasmic domain is rare. Increased expression of TGF-α and EGF has been detected in Barrett’s esophagus, EAD, and ESCC.⁸,⁹,¹⁰,¹¹,¹² EGFR overexpression may predict a poor response to chemoradiotherapy¹³,¹⁴ and is associated with decreased survival in patients with squamous cell carcinoma.¹³ Furthermore, EGFR overexpression was associated with recurrent disease and diminished overall survival in patients undergoing esophagectomy for ESCC.¹⁴,¹⁵ In contrast to EGFR, it is not clear if erbB2 overexpression is consistently found either in ESCC or EAD.

The mammalian cell cycle is regulated exquisitely by cyclins, cyclin-dependent kinases (CDK), and cyclin-dependent kinase inhibitors (CDKi such as p15, p16, p21, and p27). During G1 phase, the cyclin D1 oncogene complexes with either CDK4 or CDK6 to phosphorylate the retinoblastoma (pRb) tumor suppressor protein and, in so doing, relieves the negative regulatory effect of pRb, allowing the E2F family of transcription factors to propel the cell cycle toward the G₁/S phase transition.¹⁶ Toward the late G1 phase, cyclin E complexes with CDKs to phosphorylate p107, which is related to pRb, and liberate more E2F members to navigate the cell cycle into S phase. As with EGFR, cyclin D1 overexpression is found in premalignant lesions, such as esophageal squamous dysplasia or Barrett’s esophagus, and the majority of early-stage ESCC or EAD.¹⁷,¹⁸ Additionally, cyclin D1 overexpression correlates with poor outcomes and survival as well as poor response to chemotherapy.¹⁹,²⁰

Although cyclin D1 overexpression accounts for cyclin D1 dysregulation, other mechanisms include mutations in cyclin D1 and mutations in Fbx4, which is the E3 ligase for cyclin D1, thereby preventing degradation of cyclin D1 in the cytoplasm and reimportation into the nucleus, where it exerts its oncogenic effects.²¹

In a similar vein, p16INK4a is an early genetic alteration, via promoter hypermethylation, point mutation, or allelic deletion, in Barrett’s esophagus and EAD, but interestingly, a late event in ESCC. Loss of heterozygosity of 9p21, the locus for both p16 and p15, has been demonstrated with high frequency in both dysplastic Barrett’s epithelium and Barrett’s adenocarcinoma (90% and more than 80% of cases, respectively).²²,²³ Promoter hypermethylation, which prevents tumor suppressor function by blocking transcription, has been documented and correlates with the degree of dysplasia in Barrett’s esophagus. It is present in up to 75% of specimens with high-grade dysplasia and is found in almost 50% of patients with adenocarcinoma of the esophagus.²⁴ Point mutations of p16 in ESCC have been found and promoter hypermethylation has been noted in up to 50% of these tumors.²⁵,²⁶ Rb gene mutation is not found in either type of esophageal neoplasm, but allelic loss of 13q where the locus of the Rb gene resides is found in up to 50% of patients with Barrett’s adenocarcinoma and squamous cell carcinoma.¹⁸,²⁷ This can correlate with diminished or loss of pRb protein in Barrett’s esophagus with dysplasia, EAD, and ESCC.²⁸,²⁹

p53 is one of the most commonly mutated genes in human cancer.²²,²³,²⁴ p53 (molecular weight approximately 53 kDa) is a tumor suppressor that interrupts the G1 phase to evaluate and permit repair of damaged DNA, which may arise from environmental exposure (e.g., irradiation, ultraviolet light) or cellular stress.³⁰ In the face of irreparable damage, p53 induces apoptosis. The p53 transcription factor binds DNA to activate or suppress a large repertoire of target genes.³¹ p53 mutations induce loss of cell-cycle checkpoints and promote genomic instability. The majority of p53 mutations occur in the DNA-binding region, and more than 80% of them are missense mutations resulting in loss of wild type
p53 function.³² Wild type p53 has a short half-life and is difficult to detect by immunohistochemistry; mutation in p53 results in stabilization of the protein and allows for easier detection by immunohistochemistry.

Detection of mutated p53 protein by immunohistochemistry has been demonstrated with increasing frequency during histologic progression from Barrett’s esophagus (5%) through dysplasia (65% to 75%) to frank adenocarcinoma (up to 90%).³³,³⁴,³⁵,³⁶ Thus, p53 mutation or loss of heterozygosity appears early in Barrett’s esophagus and EAD. Both mutant p53 protein detected by immunohistochemistry and specific p53 gene mutations detected by genomic sequencing have been identified in 40% to 75% of patients with ESCC.³⁷,³⁸,³⁹,⁴⁰ The presence of a p53

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