Genetic risks and familial associations of small bowel carcinoma

Abstract

Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn's disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease". Figures, tables and schematic diagram to illustrate pathways are included in the review.

Keywords: Genetic risks; Mutations; Signaling pathways; Small intestinal adenocarcinoma; Surveillance.

Figure 1

Schematic drawing of genetic and molecular pathways predisposing to small bowel carcinoma. Wnt: Wingless-type MMTV integration site family; KRAS: Kirsten rat sarcoma viral oncogene homolog; LOH: Loss of heterozygosity; CIMP: CpG island methylator phenotype; MSI: Microsatellite instability; BRAFV600E: V-raf murine sarcoma viral oncogenes homolog B; mTOR: Mammalian target of rapamycin; TGF-β: Transforming growth factor β; IL: Interleukin; CD4TL: CD4 T-lymphocytes.

Figure 2

65-year-old male with familial adenomatous polyposis, previous total proctocolectomy 35 years ago with ileostomy adenocarcinoma: Polypoid growth at the ileostomy orifice.

Figure 3

Sixty-nine-year-old male with family history of Lynch syndrome, jejunal adenocarcinoma, viewed on small bowel enteroscopy.