The incidence of squamous cell carcinoma of the esophagus shows marked geographical variation, with a high frequency in the Caspian littoral of Iran, certain parts of the interior of China, and the Transkei region of South Africa. There is a low incidence in European and North American Caucasian populations. Oropharyngeal Tumours are also commoner in areas with a high incidence of esophageal cancer. These findings are thought to be the result of differences in exposure to ingested carcinogens rather than of major genetic factors, although the at-risk individuals who develop this cancer in these high-risk areas are predominantly of Mongol or Turkic origin. The incidence of esophageal cancer in the UK is 6 per 100,000, and it is commoner in males. Almost all (98 %) of esophageal cancers are squamous carcinomas.
Early studies suggested that genetic factors do not play a major role in most cases of esophageal cancer as there did not appear to be an increased risk to relatives of index cases (Mosbech and Videbaek 1955), and recent studies in the United States have been in agreement (Dhillon et al. 2001). However other studies, particularly those in high-incidence regions, such as China, have come to the conclusion that the familial occurrence of esophageal cancer probably does have a Mendelian basis, with both autosomal dominant (Zhang et al. 2000; Guohong et al. 2010) and recessive models favored. A genome-wide search indicated that chromosome 13 could harbor such a gene, but sequence analysis of known candidate genes, such as BRCA2, has been inconclusive (Hu et al. 2002, 2004).
Interestingly, gene expression studies indicate that true differences exist between familial and nonfamilial esophageal cancer, suggesting that there are susceptibility genes to be found (Su et al. 2003).
The autosomal dominant condition of late-onset tylosis (keratosis palmaris et plantaris), with hyperkeratosis of the palms and soles from late childhood to adolescence, is associated with a high incidence of esophageal cancer (Shine and Alison 1966; Risk et al. 2002). Tylosis with onset in infancy does not seem to be associated with any such increased cancer risk. Thickening of the skin of the pressure areas on the soles of the feet is seen, and oral leukokeratosis and follicular hyperkeratosis occur. The risk of esophageal cancer reaches 95 % by 63 years of age, and the mean age at diagnosis of the cancer is 45 years of age. Prophylactic esophagectomy with interposition of a segment of colon has been suggested for affected individuals. If prophylactic esophagectomy has not been performed, then annual esophagoscopy is recommended, and immediate esophagectomy is advisable if dysplasia is detected. The gene for this condition was mapped to chromosome 17q, and a presumed gain-of-function mutation in RHBDF2 has been reported as the cause (Hennies et al. 1995; Kelsell et al. 1996; Langan et al. 2004; Blaydon et al. 2012; Saarinen et al. 2012).
There is an increased risk of esophageal cancer in Fanconi anemia (Alter 1996; Rosenberg et al. 2003) and possibly also in epidermolysis bullosa, dyskeratosis congenita, and congenital abnormalities of the esophagus, such as strictures. In support of the earlier epidemiological data, mutations in genes in the Fanconi anemia pathway have been associated with esophageal cancer in Iran – most notably, BRCA2 (FANCD1), where the p. Lys3326X mutation was present in 27 of 746 esophageal squamous cell cancer cases and in 16 of 1,373 controls (OR = 3.38, 95 % CI = 1.97–6.91, P = 0.0002) (Akbari et al. 2011). This is a notable finding because this particular BRCA2 mutation is generally not thought to be a cause of breast cancer susceptibility.
The risk of esophageal cancer increases with celiac disease and is more common in the adult-onset form, but is probably uncommon when celiac disease is diagnosed and treated in childhood or infancy. There is an increased risk of esophageal cancer in achalasia. This condition is not usually genetic, but its familial occurrence has been described occasionally with some evidence of an autosomal recessive subgroup (Frieling et al. 1988; Gockel et al. 2010). Nevertheless it may occur rarely as part of a genetic condition (autosomal recessive), characterized by achalasia, alacrimia, and sensorimotor polyneuropathy (Achalasia–Addisonianism–Alacrimia syndrome, also known as Allgrove syndrome), and the responsible gene, AAAS, has been identified (Kasirga et al. 1996; Handschug et al. 2001).
There is also an increased risk of adenocarcinoma of the esophagus (possibly 10 %) in Barrett esophagus, in which columnar rather than squamous epithelium is found with chronic ulcerative esophagitis. Although this is usually sporadic, some familial cases have been described, and 70 families have recently been reported (Drovdlic et al. 2003). Importantly, there was no excess of extra-esophageal cancers in these families. In unselected individuals with Barrett esophagus, it is among older males that most familial cases are encountered (Chak et al. 2002). Germline mutations in MSR1 have been reported in a small proportion of patients with Barrett esophagus/esophageal cancer (Orloff et al. 2011).
In tylosis, annual esophagoscopy is recommended unless prophylactic esophagectomy has been performed, and because of the high risk of cancer in this disorder, immediate esophagectomy is advisable if dysplasia is detected. However, in other conditions in which the risk of carcinoma is less, the appropriate course of action if an abnormality is found may not be so clear, and results from an observational study of individuals undergoing surveillance for Barrett esophagus found that there was no impact on overall mortality (MacDonald et al. 2000). Nevertheless, those with a family history are likely to be screened by endoscopy even if they do not have long-segment disease. Screening for esophageal cancer by endoscopy with multiple biopsies to detect dysplasia is performed in some high-risk areas in China (Spigelman and Phillips 1991).