Gastric (Stomach) cancer is one of the most common cancer types world-wide. As the fourth most common cancer worldwide and the second most common cause of cancer death, it is an important public health problem, particularly in Asia where is is quite common.
There are two major subtypes of gastric cancer that can be recognized under the microscope: "intestinal" and "diffuse." The intestinal type seems to be associated with Helicobacter pylori infection and is particularly common in some high risk geographic regions, including Asia.
In contrast, the diffuse type seems unrelated to the presence of H. pylori and has a much more uniform geographical distribution.
We've known for a long time that there is an hereditary component to risk for at least some diffuse gastric cancer cases. A major breakthrough came when mutations in the CDH1 gene were found to be responsible for a familial form of diffuse gastric cancer: "Hereditary Diffuse Gastric Cancer." The CDH1 gene provides the coding information necessary for our bodies to make a protein called "E-cadherin," which is important in the molecular connections between adjacent cells in the stomach, the breast, and also other areas of the body. Loss of E-cadherin function - associated with mutations in the CDH1 gene - is seen in diffuse type cancers of the stomach and also a specific type of breast cancer: invasive lobular breast cancer.
Individuals inheriting a familial mutation in CDH1 have an approximately 75% lifetime risk for developing diffuse gastric carcinoma and women with an inherited CDH1 mutation have about a 40% lifetime risk for developing lobular breast cancer.
Nevertheless, inherited Hereditary Diffuse Gastric Carcinoma with mutations in CDH1 is pretty rare. With this in mind, some research groups have been looking for other genes that might be involved in risk for diffuse gastric carcinoma, particularly the non-familial type (i.e., diffuse gastric carcinoma in an individual without a family history of this type of cancer).
Recently, a Japanese research group, "The Study Group of Millennium Genome Project for Cancer," reported in Nature Genetics (abstract available here) the results of a new study demonstrating the involvement of the PSCA gene in risk for diffuse type gastric cancer.
The authors focused the study design on "sporadic" (i.e., non-familial or occurring in someone without a family history of the disease) diffuse gastric cancer. In other words, they figured that an individual's genes might influence risk for this cancer type even in the absence of a family history of the disease.
A genome-wide association study (GWAS) performed initially in 188 people with sporadic gastric cancer and 752 controls revealed an association of a single nucleotide polymorphism (rs2976392) in the gene PSCA (aka prostate stem cell antigen) with diffuse gastric cancer. Re-sequencing of the PSCA region in the affected individuals revealed a number of SNPs that could potentially be responsible; however, it appears that a non-synonymous SNP (i.e., one that changes an amino acid in the PSCA protein), rs2294008, is most likely responsible for conferring disease risk. As it can change the first amino acid from methionine (which must be the first amino acid when proteins are produced) to threonine, it appears likely to affect both the efficiency of PSCA protein production and also the length of the resultant protein.
Interestingly, the authors did include some cases of intestinal type stomach cancer in the analysis and showed that the effect of genetic variation in PSCA was much stronger on risk for diffuse gastric cancer than for the intestinal type.
Finally, in addition to replicating their results on a second set of samples in Japan, they also showed an association of PSCA SNPs with diffuse gastric cancer in Korean individuals.
So, what are the clinical implications? As the allele-specific odds ratios are less than 2, these SNPs are unlikely to have a major impact on clinical practice in the near term. They do teach us something interesting about gastric cancer causation and also - importantly - may identify a novel drug target or pathway in this disease. Interestingly, the risk variants exist as "major alleles" in the Japanese population. This means that most people carry them. Thus, it might explain some of the increased frequency of diffuse gastric cancer in this population.
Additionally, as the authors did not have information about Helicobacter pylori infection for most study patients, is is unclear whether the PSCA SNPs directly affect disease risk or might instead influence an individual's susceptibility to H. pylori infection, which is itself a risk factor for gastric cancer development. Perhaps further studies will be able to clarify this point.
Genes of Interest
Key References
Brooks-Wilson AR et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. Journal of Medical Genetics 41: 508-17, 2004.
Guilford P et al. E-cadherin germline mutations in familial gastric cancer. Nature 392: 402-5, 1998.
Kaurah P, Huntsman DG. (Updated 31 August 2006). Hereditary diffuse gastric cancer. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at http://www.genetests.org.
Pharoah PD et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121: 1348-53, 2001.
The Study Group of Millenium Genome Project for Cancer. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nature Genetics; published online 18 May 2008; doi:10.1038/ng.152.
