Researchers have identified germline mutations in three genes that appear to be associated with Barrett's esophagus and esophageal adenocarcinoma, according to a report in the July 27 issue of JAMA.
The mutations, however, only accounted for a small proportion (11%) of cases of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) in this study. Mutations in the MSR1 gene accounted for 7% of cases, and mutations in either ASCC1 or CTHRC1 accounted for approximately 2% each, said Mohammed Orloff, Ph.D., of the Genomic Medicine Institute and Taussig Cancer Institute at the Cleveland Clinic, and his associates.
Most cases of BE and EAC are thought to be sporadic rather than inherited, but in the past few decades clustering of cases in some families has been observed, supporting the existence of predisposition genes as well, the authors explained.
"The discovery of germline mutations in a gene or genes that predispose to BE/EAC may have ramifications regarding cancer risk assessment, genetic counseling, premorbid diagnosis, and targeted surveillance and management, and also [may] add to the fundamental understanding of the pathophysiology of sporadic BE and EAC," they wrote.
Over the course of 5 years, the investigators performed a series of genetic studies that led to their discovery of these three germline mutations.
They began by recruiting 298 adults with histologically proven Barrett’s esophagus and/or esophageal adenocarcinoma, as well as families with two or more cases of these disorders, from 16 academic and community hospitals and clinics across the United States. They found and genotyped 21 pairs of siblings in which both siblings were affected and 11 pairs of siblings in which only one sibling was affected.
The researchers identified what appeared to be significant genomic regions in these subjects, then validated these "potentially interesting" regions and performed fine mapping in a separate series of 176 patients with BE and/or EAC and 200 ancestry-matched population control subjects, Dr. Orloff and his associates said. Only white patients of northern or western European descent were included.
The investigators integrated these results with publicly available data on somatic gene expression derived from 19 other affected patients to develop a list of 12 biologically plausible candidate genes to be scanned in more detail for germline mutations. This analysis showed that three candidate genes were significantly associated with BE or EAC (P less than .001 for each). The genes were MSR1 (macrophage scavenger receptor 1), ASCC1 (activating signal cointegrator 1 complex subunit 1), and CTHRC1 (collagen triple-helix repeat-containing 1).
A similar mutational analysis performed in a separate series of 58 cases obtained from outpatient endoscopy clinics confirmed these results.
"These three genes together accounted for 11% of our cases, reflecting what is normally considered a moderate- to high-penetrance genetic load for a disease," Dr. Orloff and his colleagues noted (JAMA 2011;306:410-19).
No mutations of these three genes were found in a pooled group of 264 control subjects.
"MSR1, on chromosome 8p22, encodes the class A macrophage scavenger receptor, which are macrophage-specific trimeric integral membrane glycoproteins implicated in many macrophage-associated, hormonal, and pathological processes, including inflammation, innate and adaptive immunity, oxidative stress, and apoptosis," they noted.
ASCC1 is thought to link inflammatory pathways to tumor suppression pathways. CTHRC1 is expressed in tissue repair processes; it may play a role in the host response to GERD and may predispose carriers to having decreased sphincter tone in the lower esophagus.
"In summary, germline mutations in MSR1, ASCC1, and CTHRC1 in patients with BE/EAC appear physiologically relevant to [these disorders], encoding proteins involved in apoptosis, innate immunity, polarity, and mobility that affect inflammatory and [other] pathways."
Larger studies are needed to determine whether genotyping to hunt for mutations in these genes and their variants would be useful in assessing people’s risk of developing BE or EAC, as well as in diagnosing the cancer earlier, when it is more responsive to treatment, the researchers said.
This study was funded in part by the M. Frank and Margaret Domiter Rudy Endowment of the Cleveland Clinic Taussig Cancer Institute and by grants from the National Cancer Institute and National Institutes of Health. No relevant financial conflicts of interest were reported.