Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: Implications for tumorigenesis

Abstract

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen-BRCA1-SSTR2-D17S2058-D17S929-D17S722-+ ++D17S937-D17S802-tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24-proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors.

BRCA1/Trp53 heterozygosity and replication stress drive esophageal cancer development in a mouse model

“…Furthermore, the overall esophageal squamous cell carcinoma (ESCC) risk in BRCA1 carriers is significant (relative risk [RR] of 2.9 [95% CI 1.1 to 6.0]) ( 5 , 6 ). This is in keeping with the observation that a relatively frequent loss of heterozygosity (LOH) is detected in the BRCA1 -containing region of chromosome 17 in squamous cell carcinoma of the esophagus ( 7 – 9 ).…”

SPT6 loss Permits the Transdifferentiation of Keratinocytes into an Intestinal Fate that Recapitulates Barrett’s Metaplasia

“…(iii) Third, our findings, together with the evidence provided by Li et al suggest a mechanism for initiation of BE while being able to connect the dots between physiological triggers of the disease, i.e., chronic acid reflux (Figure 2G). For example, acid exposure has been shown to promote intestinal differentiation in both BE explants 19 and BE-derived adenocarcinoma cell lines 20 , and here we show that acid exposure reduces SPT6 mRNA and protein in a dose dependent manner.…”

“…Notably, loss of p53, which is located on the short arm of Chr 17p13, signals risk for BE to adenocarcinoma progression 32 . Unlike the timing of loss of tp53, which happens later in BE-to-cancer progression, microdeletions in the distal long arm of Chr 17q has been proposed as early event in BE initiation 33 . Because microsatellites might be sensitive indicators of disrupted mechanisms and indicate a propensity to mutagenesis, we speculate that microdeletions at Chr17q11.2 could impact SPT6 expression and trigger the transdifferentiation of keratinocytes into BE.…”

SPT6 loss permits the transdifferentiation of keratinocytes into an intestinal fate that resembles Barrett’s metaplasia

“…Notably, loss of p53, which is located on the short arm of Chr 17p13, signals risk for BE to adenocarcinoma progression ( Kastelein et al., 2013 ). Unlike the timing of loss of tp53, which happens later in BE-to-cancer progression, microdeletions in the distal long arm of Chr 17q has been proposed as early event in BE initiation ( Petty et al., 1998 ). Because microsatellites might be sensitive indicators of disrupted mechanisms and indicate a propensity to mutagenesis, we speculate that microdeletions at Chr17q11.2 could impact SPT6 expression and trigger the transdifferentiation of keratinocytes into BE.…”