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Review
. 2024 Jun 26;46(7):6440-6471.
doi: 10.3390/cimb46070385.

Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes

María Jesús Fernández Aceñero  1   2 , Cristina Díaz Del Arco  1   2
Affiliations
Review

Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes

María Jesús Fernández Aceñero et al. Curr Issues Mol Biol. .

Abstract

Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.

Keywords: cancer; colorectal cancer; familial syndromes; gastric cancer; gastrointestinal tract; genetic variant; hereditary; management; mutation; next-generation sequencing.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Hereditary gastric cancer syndromes and related genes. GC: gastric cancer; HDGC: hereditary diffuse gastric cancer; GAPPS: gastric adenocarcinoma and proximal polyposis of the stomach; FIGC: familial intestinal gastric cancer; FAP: familial adenomatous polyposis; MUTYH: MUTYH-associated polyposis, PTEN-hamartoma: PTEN hamartoma tumor syndrome; HBOC: hereditary breast and ovarian cancer; DNA MMR: DNA mismatch repair genes. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 2
Figure 2
Laurén subtypes predominantly linked to hereditary gastric cancer syndromes. GC: gastric cancer; GAPPS: gastric adenocarcinoma and proximal polyposis of the stomach; FIGC: familial intestinal gastric cancer, HDGC: hereditary diffuse gastric cancer. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 3
Figure 3
Adherens junction. E-cadherins have extracellular, transmembrane, and intracellular domains. They form homodimers, and the intracellular domain interacts with adaptor proteins such as p120 and catenins to connect with the actin cytoskeleton. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 4
Figure 4
Activated canonical Wnt pathway. The Wnt protein binds to the extracellular domain of a Frizzled family receptor, alongside various co-receptors. Upon activation, it triggers a cytoplasmic cascade, leading to the accumulation of β-catenin, its translocation to the nucleus, and the transcription of target genes. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 5
Figure 5
Physiological roles of p53. The p53 protein is a transcription factor that responds to various stimuli and, as a result, can induce cell cycle arrest, DNA repair, senescence, or programmed cell death, among other processes. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 6
Figure 6
Main familial/hereditary syndromes of colorectal cancer. CRC: colorectal cancer; FAP: familial adenomatous polyposis. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
Figure 7
Figure 7
Inactive canonical Wnt pathway. The absence of Wnt ligands leads to the phosphorylation of β-catenin by the destruction complex, comprising Axin, APC, and several kinases. This phosphorylated β-catenin is subsequently degraded by the proteasome. Additionally, without nuclear β-catenin, a repressive complex (TCF-TLE) inhibits gene transcription. Image created with Biorender.com (https://www.biorender.com/, accessed on 1 May 2024) under an individual license (Dr. Díaz del Arco).
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