gastrointestinal (GI) cancer is a heterogeneous cancer that tends to occur in the more common sporadic forms rather than the rare inherited forms. The process of initiation and formation of neoplastic cells in the GI tract can be classified into four main mechanisms: (i) inherited transmission of mutations; (ii) exposure to different carcinogens; (iii) chronic inflammatory conditions/microbial dysbiosis; and (iv) sporadic mutations and epigenetic changes [24].

Hereditary GI Cancers

Hereditary GI cancers represent a phenotypically diverse group of diseases involving malignant tumors of the digestive tract, extra-GI cancers, and benign abnormalities characterized by inherited genetic mutations transmitted from parent to child. However, no more than 3%–5% of GI cancers have shown a clear hereditary basis [25]. The esophagus, stomach, colon, small intestine, and pancreas have been identified as the organs most likely to inherit germline mutations [24]. The best known inherited malignant tumors are associated with the GI tract, representing monogenic hereditary diseases that result from mutations in a single gene [26]. Despite the specific differences in the genes involved, inherited GI cancers share a common set of characteristics: (i) the majority of GI cancers are detectable in the early stages of life; (ii) these cancers follow an autosomal dominant inheritance mechanism in which the neoplasm occurs in 1st degree relatives; and (iii) the formation of multiple tumors [26,27]. In the hereditary form of GI cancers, the first genetic mutation in one of the alleles of a predisposition gene is acquired at the time of conception, and the somatic mutation of the second allele is then acquired via environmental insult, lifestyle practices or other exogenous factors (Figure 1). Once the two alleles of a specific predisposition gene are mutated, gene function is completely inactivated, leading to carcinogenesis. Compared to the sporadic form of GI cancer, which requires two somatic events during the inactivation of the predisposition gene, hereditary cancers present a higher risk because they need only one somatic mutation event, which explains the early onset of hereditary cancers [28]. In parallel with the advancement of DNA technologies, the genetic mutations responsible for hereditary GI cancers have been widely documented (Table 1). These hereditary GI cancers include Cowden syndrome, MUTYH-associated polyposis, hereditary pancreatic cancer, Lynch syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis (FAP), attenuated FAP, serrated polyposis syndrome, and hereditary gastric cancer. Cancer-causing mutations can be initiated in three main classes of predisposition genes, oncogenes, tumor suppressor genes, and DNA repair genes, which are involved in establishing genetic stability.

Figure 1. Two-hit theory of the initiation of hereditary and non-hereditary cancer. People with a hereditary susceptibility to GI cancers harbor an inherited genetic mutation on one of the chromosomes at the time of conception and receive the 1st somatic mutation due to the endogenous (e.g., chronic inflammation) or exogenous (e.g., exposure to carcinogens) rare events which in turn inactivate the full function of the respective gene and initiate neoplastic transformation. Non-inherited forms of GI cancer occur by acquiring two somatic mutations in later life, resulting in the inactivation of a gene leading to the initiation of malignancy.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21186555