Genesis and Progression of GI Cancer – a Genetic Disease - Gastric, Pancreatic Cancer

Chapter 1 - Biology of Cancer Development in the GI Tract

Gastric Cancer

The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification.

Most gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori and Epstein–Barr virus (EBV). A minority are associated with germline mutation in E-cadherin (CDH1) or MMR genes, whereas sporadic MMR-deficient gastric cancers have epigenetic silencing of MLH1 in the context of CIMP.

Gene expression or DNA sequencing have been used in molecular profiling of gastric cancer, but have not led to a clear biological classification scheme. More recent studies by The Cancer Genome Atlas (TCGA) have permitted more precise molecular classification of gastric cancer by identifying dysregulated pathways and candidate drivers of distinct classes.

Pancreatic Cancer

Pancreatic adenocarcinoma presents a progression from distinct types of precursor lesions, a propensity for both local invasion and distant metastasis, an extensive stromal reaction (desmoplasia) resulting in a hypovascular and hypoxic microenvironment, reprogramming of cellular metabolism, and evasion of tumour immunity.

There is a stepwise progression of pancreatic intraepithelial neoplasia (PanIN) from low grade to high grade in types 1, 2 and 3.

These types are associated with accumulating genetic alterations.

More than 90% of cases of PanIN of all grades have KRAS mutations. Mutational inactivation of the CDKN2A, p53 and SMAD4 tumour suppressors occurs later in type 2 and type 3 lesions of PanIN.

In addition, 40%–80% have activating mutations in GNAS and more than 50% have inactivation of RNF43 (an antagonist of Wnt signalling).

The pancreatic adenocarcinoma genome is also characterised by diverse, large-scale chromosomal changes with frequent amplifications, deletions and rearrangements.

Revision Questions

  1. Are there any gastric cancers with MSI?
  2. How are diffuse type gastric carcinomas molecularly defined?
  3. What is the most common molecular alteration in pancreatic carcinomas?
Last update: 07 July 2016