Other entities represented in this entry:
SNOMEDCT: 372138000; ORPHA: 99977; DO: 5041;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p24.1 | Esophageal cancer, somatic | 133239 | 3 | TGFBR2 | 190182 | |
| 8p21.3 | Esophageal squamous cell carcinoma, somatic | 133239 | 3 | LZTS1 | 606551 | |
| 13q12.13 | Esophageal carcinoma, somatic | 133239 | 3 | RNF6 | 604242 | |
| 16q23.1-q23.2 | Esophageal squamous cell carcinoma, somatic | 133239 | 3 | WWOX | 605131 | |
| 18q21.2 | Esophageal carcinoma, somatic | 133239 | 3 | DCC | 120470 |
A number sign (#) is used with this entry because of evidence that several genes are involved in the susceptibility to, as well as in the origin and progression of, esophageal cancer.
Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is one of the most common cancers worldwide. Both environmental and genetic risk factors play a role in the pathogenesis of the disorder. In Europe and North America, heavy smoking, alcohol consumption, and increased body mass index (BMI) are the main environmental risk factors. In contrast, the particularly high incidence of ESCC in some areas of China, central Asia, and southern Africa is associated with nutritional deficiencies, high intake of nitrosamine-rich or pickled vegetables, and low socioeconomic status; smoking, alcohol consumption, and BMI play a lesser role in these populations. There is a tendency for familial aggregation of ESCC in high-risk geographic areas, suggesting a genetic component to increased susceptibility. Gastric cardia adenocarcinoma is another common type of cancer in China that shows similarities to ESCC in terms of geographic distribution and environmental risk factors (summary by Wang et al., 2010 and Abnet et al., 2010).
Genetic Heterogeneity of Susceptibility to Esophageal Cancer
See a variant in the ADH1B gene (103720.0001) for discussion of a possible genetic association with protection against squamous cell aerodigestive tract cancer, including esophageal cancer, in alcohol drinkers. See a variant in the ALDH2 gene (100650.0001) for discussion of a possible genetic association with increased risk for esophageal cancer in alcohol drinkers due to interaction between variants in the ADH1B and ALDH2 genes.
See the S100A14 gene (607986) on chromosome 1q21 for a discussion of a possible association between variation in that gene and susceptibility to esophageal squamous cell carcinoma among smokers.
Genetic Heterogeneity of Somatic Mutations in Esophageal Cancer
Somatic mutations in several different genes have been found in esophageal cancer tissue. These genes include TP53 (191170), CDKN2A (600160), DEC1 (604767), DCC (120470), DLEC1 (604050), TGFBR2 (190182), LZTS1 (606551), RNF6 (604242), WWOX (605131), APC (611731), and RUNX3 (600210).
Somatic Loss of Heterozygosity in Tumor Tissue
The TP53 gene and the RB1 gene (614041) have been shown to be abnormal in esophageal cancers (Blount et al., 1991; Boynton et al., 1991).
Boynton et al. (1992) used the polymerase chain reaction (PCR) and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for LOH of the APC gene, the MCC gene (159350), or both. Loss of 1 allele was detected in 77% of 26 informative cases. Both squamous cancers and adenocarcinomas were equally represented among the tumors showing LOH.
Sano et al. (1991) observed a high incidence of LOH of the chromosome 5q region in well-differentiated, but not in poorly differentiated, gastric adenocarcinomas. Cancers of the gastric cardia, but not distal gastric cancers, show anatomic, epidemiologic, and pathologic similarities to esophageal adenocarcinoma.
Using PCR amplification of microsatellite regions in DNA from 11 epithelial dysplasias of the esophagus and 21 early squamous cell carcinomas, Mori et al. (1994) detected frequent LOH on 3p21.3 and 9q31, even in low-grade dysplasias. In contrast, they observed frequent LOH on 9p22 and 17p13, the latter being the site of the TP53 locus, only in high-grade dysplasias and carcinomas and not in any low-grade dysplasias. DLEC1 is located on 3p22-p21.3 and DEC1 is located on 9q32.
Hu et al. (2000) performed a genomewide scan for LOH in ESCC and showed it was very frequent in several regions, including 3p, 5q, 9p, 9q, and 13q.
Wang et al. (2003) found that 12 of 43 (28%) primary esophageal carcinomas showed LOH at chromosome 7q31-q35. These included 4 of 18 squamous cell carcinomas and 8 of 25 adenocarcinomas. The data suggested that LOH at 7q31-q35 is involved in the origin or progression of at least a subset of esophageal carcinomas, but studies of the suppressor of tumorigenicity 7 gene (ST7; 600833), which is located in this region, indicated that it is not the target of this somatic event.
Genomewide Association Studies
In a genomewide association study of 1,077 Chinese Han patients with ESCC and 1,733 Chinese Han controls, with replication in an additional 7,673 Chinese Han patients and 11,013 Chinese Han controls, as well as in 303 patients and 537 controls of Chinese Uygur-Kazakh descent, Wang et al. (2010) identified significant disease associations with 2 previously unknown loci. A nonsynonymous SNP (his-to-arg; rs2274223) in exon 26 of the PLCE1 gene (608414) on chromosome 10q23 was significantly associated in Chinese Han (combined p value = 7.46 x 10(-56); odds ratio (OR), 1.43) and in Chinese Uygur-Kazakh (p value = 5.70 x 10(-4); OR, 1.53). A SNP (rs13042395) in the C20ORF54 gene (613350) on chromosome 20p13 was also significantly associated in Chinese Han (combined p value = 1.21 x 10(-11); OR, 0.86) and in Chinese Uygur-Kazakh (p value = 7.88 x 10(-3); OR, 0.66). Association with gastric cardia adenocarcinoma was also confirmed in 2,766 Chinese Han patients and 11,013 Chinese Han controls for rs2274223 (p value = 1.74 x 10(-39); OR, 1.55) and rs13042395 (p value = 3.02 x 10(-3); OR, 0.91). Wang et al. (2010) noted that PLCE1 may regulate cell growth, differentiation, apoptosis and angiogenesis, whereas C20ORF54 is responsible for transporting riboflavin, a deficiency of which has been documented as a risk factor for ESCC and gastric cardia adenocarcinoma.
In a combined analysis of 5 genomewide association studies involving 2,240 patients with gastric cancer, 2,115 patients with ESCC, and 3,302 controls, all of Chinese ethnicity, Abnet et al. (2010) found significant associations between rs2274223 (R1927H) in the PLCE1 gene and gastric cardia cancer (p = 4.19 x 10(-15); OR, 1.57) and ESCC (p = 3.85 x 10(-9); OR, 1.34). They also identified a second nonsynonymous PLCE1 SNP (rs3765524; I1777T) that was significantly associated with gastric cardia cancer (p = 7.36 x 10(-15); OR, 1.56) and ESCC (p = 1.74 x 10(-9); OR, 1.35). Abnet et al. (2010) stated that further work was needed to determine whether these SNPs were functionally important.
Wu et al. (2012) conducted a genomewide association study and a genomewide gene-environment interaction analysis of esophageal squamous cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls, with independent validation in 8,092 cases and 8,620 controls. Wu et al. (2012) identified 6 new esophageal squamous cell carcinoma susceptibility loci, of which 4, at chromosomes 4q23, 16q12.1, 22q12, and 3q27, had a significant marginal effect (p = 1.78 x 10(-39) to p = 2.49 x 10(-11)) and 2 of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction p p(G x E) = 4.39 x 10(-11) and p(G x E) = 4.80 x 10(-8), respectively). Wu et al. (2012) confirmed the association of ALDH2 on 12q24 to ESCC, and a joint analysis showed that drinkers with both ADH1B and ALDH2 risk alleles had a 4-fold increased risk for ESCC compared to drinkers without these risk alleles.
Esophageal cancer is very common in many areas of China, especially the north. Whereas the disease ranks as the ninth most frequent cancer in the world, in China it is the fourth most frequent cause of death from malignant tumors. Zhang et al. (2000) conducted a pedigree survey of 225 patients affected by esophageal cancer in Yangquan, Shanxi Province, to explore the mode of inheritance in this moderately high-incidence area of northern China. They found that mendelian autosomal recessive inheritance of a major gene that influences susceptibility to esophageal cancer provided the best fit to the data. In the best-fitting recessive model, the frequency of the disease allele was 0.2039. There was a significant sex effect on susceptibility to the disease. The maximum cumulative probability of esophageal cancer among males with the AA genotype was 100%, but among females it was 63.5%. The mean age at onset for both men and women was 62 years. The age-dependent penetrances for males with the AA genotype by the ages of 60 and 80 years were 41.6% and 95.2%, respectively, whereas for females they were 26.4% and 60.5%, respectively. Incorporating environmental risk factors--such as cigarette smoking, pipe smoking, alcohol drinking, eating hot food, and eating pickled vegetables--into the models did not provide significant improvement of the fit of the models to these data.
Kawakami et al. (2000) found hypermethylation of the promoter region of the APC gene in tumor tissue of 48 of 52 (92%) patients with esophageal adenocarcinoma, 16 of 32 (50%) patients with esophageal squamous cell carcinoma, and 17 of 43 (39.5%) patients with Barrett metaplasia (see 109350), but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 25% of the adenocarcinoma patients and over 6% of the squamous cell carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival. Similarly, the CDKN2/p16 locus frequently shows LOH and hypermethylation in esophageal tumors, whereas inactivating point mutations affecting this gene are relatively rare. The critical genes targeted by hypermethylation in human cancers include the MLH1 gene (120436), the estrogen receptor (ESR1; 133430), and progesterone receptor (607311) genes, and the E-cadherin gene (192090).
Berman et al. (2003) demonstrated that a wide range of digestive tract tumors, including most of those originating in the esophagus, stomach, biliary tract, and pancreas, but not in the colon, display increased hedgehog pathway activity, which is suppressible by cyclopamine, a hedgehog pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumors in vivo. Unlike tumors in Gorlin syndrome (109400), pathway activity and cell growth in these digestive tract tumors are driven by endogenous expression of hedgehog ligands, as indicated by the presence of Sonic hedgehog (600725) and Indian hedgehog (600726) transcripts, by the pathway- and growth-inhibitory activity of a hedgehog-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added hedgehog ligand. Berman et al. (2003) concluded that their results identified a group of common lethal malignancies in which hedgehog pathway activity, essential for tumor growth, is activated not by mutation but by ligand expression.
Lo et al. (2007) identified a 1.61-Mb tumor suppressive critical region on chromosome 3p14.2 encompassing the ADAMTS9 gene (605421) by using microcell-mediated chromosome transfer to a human esophageal squamous cell cancer line SLMT1 and subsequent mouse tumorigenicity assays. Tumor-suppressed hybrid cells showed normal ADAMTS9 expression levels, whereas 15 of 16 esophageal cancer cell lines showed decreased or absent expression. Downregulation of ADAMTS9 was also found in 40 to 50% of primary esophageal tumor tissues. ADAMTS9 promoter hypermethylation was detected in the cell lines that showed decreased or absent expression, and demethylation drug treatment resulted in ADAMTS9 reexpression. The findings suggested that ADAMTS9 may contribute to the development of esophageal cancer.
Bass et al. (2009) showed that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas of the lung and esophagus contains the transcription factor gene SOX2 (184429), which is necessary for normal esophageal squamous development (Que et al., 2007) and differentiation and proliferation of basal tracheal cells (Que et al., 2009), and cooperates in induction of pluripotent stem cells, as summarized by Bass et al. (2009). Bass et al. (2009) found that SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 in this study cooperated with FOXE1 (602617) or FGFR2 (176943) to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. Bass et al. (2009) concluded that these characteristics identified SOX2 as a lineage-survival oncogene in lung and esophageal squamous cell carcinoma.
Somatic Mutations
Using a panel of 56 pairs of ESCC primary tumors and their matched normal DNAs, Li et al. (2001) refined an LOH locus to chromosome 13q12.11. Lo et al. (2002) screened for mutations in 2 genes located within an 800-kb region of this chromosome segment, ATP8A2 (605870) and RNF6 (604242), in 24 ESCC primary tumors and 16 tumor cell lines by direct sequencing of the PCR products amplified from each exon. They detected no mutations in ATP8A2, but identified 3 somatic mutations in the RNF6 gene (604242.0001-604242.0003).
Li et al. (2002) showed that between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression.
In 86 samples from gastric tumors, Wei et al. (2005) found a loss of or substantial decrease of RUNX3 protein expression compared to normal gastric mucosa (p less than 0.0001). Decreased RUNX3 expression was significantly associated with decreased survival (p = 0.0005). Studies in gastric cancer cell lines also showed loss of or decreased RUNX3 expression, and restoration of RUNX3 induced cell cycle arrest and apoptosis, resulting in suppression of cancer cell growth. The findings implicated RUNX3 as a tumor suppressor gene in gastric cancer.
The Cancer Genome Atlas Research Network (2017) performed a comprehensive molecular analysis of 164 carcinomas of the esophagus derived from Western and Eastern populations. Esophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did esophageal adenocarcinomas. Analyses identified 3 molecular subclasses of esophageal squamous cell carcinomas, but none showed evidence for an etiologic role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 (168461) and SOX2 (184429) and/or TP63 (603273), whereas ERBB2 (164870), VEGFA (192240), GATA4 (600576), and GATA6 (601656) were more commonly amplified in adenocarcinomas. Esophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in esophageal adenocarcinomas.
Morrison et al. (2009) found that mice with targeted deletion of the Ihpk2 gene (606992) had a 4-fold increased incidence of invasive squamous cell carcinoma in the oral cavity and esophagus after chronic exposure to a carcinogen in drinking water compared to wildtype mice. Paradoxically, Ihpk2-knockout mice displayed relative resistance to ionizing radiation and showed enhanced survival following total body irradiation. Fibroblasts derived from Ihpk2-knockout mice showed resistance to antiproliferative effects of beta-interferon and increased colony forming units following ionizing radiation; this phenomenon was associated with accelerated DNA repair. Wildtype Ihpk2, but not the enzymatically inactive variant, was able to reverse the knockout phenotype, suggesting that the enzymatic activity contributes to radiosensitivity. Tissues from Ihpk2-knockout mice showed relative overexpression of putative oncogenes, Ttf1 (NKX2-1; 600635) and Twistnb (Polr1f; 608312), as well as downregulation of 2 putative tumor suppressor genes Dusp16 (607175) and Ext2 (608210).
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