Cancer and Your Genes

Stomach Cancer and Your Genes: New Evidence for a Common Gene Variant Influencing Risk for Diffuse Gastric Cancer

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

CDH1

PSCA

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.

 

Colon Cancer Risk: More Evidence for Common Disease, Common Gene Hypothesis

We know from both population-based epidemiologic studies and from twin studies that our genes make a substantial contribution to risk for colorectal (aka colon) cancer.  Although there are several relatively uncommon familial colon cancer predisposition syndromes (which account for <5% of all colon cancer) with known genes involved, progress towards unraveling genomic variants involved in the more common, run-of-the-mill colon cancer cases has been slower in coming. 

However, a study published recently in the journal Nature Genetics reports significant progress in this regard.  This study is one of a flurry of genome-wide association studies (GWAS) - which utilize a study design made possible by recent advances in our ability to simultaneously examine an individual's genotype at hundreds of thousands of sites of single nucleotide polymorphisms (SNPs).

Pursuing the idea that variation in colon cancer risk may be due to relatively common low risk SNPs (perhaps in combination), many of the same authors (a group led by Richard Houlston and Ian Tomlinson) had reported in the August 2007 Nature Genetics that a SNP located on chromosome 8 was associated with colon cancer.  Although statistical support was strong, it is important to keep in mind that the risk to individuals with the variant SNP (whether they have one copy or two) was modest.  Odds ratios were 1.27 for heterozygotes (with one copy of the risk variant) and 1.47 for homozygotes (who carry the risk variant on both copies of chromosome 8).  There were also reports from other groups in Nature Genetics about colon cancer risk and this region of chromosome 8. 

Now, in the new paper published online in the November 2007 issue of Nature Genetics, the group led by Houlston and Tomlinson focused on another strong signal from their genome-wide association study.  They identified three SNPs in a gene called SMAD7 that were very significantly associated with colon cancer risk.  Interestingly, as with the results from a number of other recent GWAS studies, the significant SNPs were intronic (i.e., located in an intron, in between the exons which are the stretches of DNA with the information coding for amino acids, the protein building blocks).  As is often the case, the functional SNP at this locus is unknown at this point. 

SMAD7 is also known as "mothers against decapentaplegic homolog 7."  Unfortunately for those of us who have to deal with this stuff clinically, the drosophila (fruitfly) genetics community has a tradition of picking names of this sort.  Nevertheless, the available information about SMAD7 function within the cell suggests that it is quite plausible as a colon cancer risk gene.  Specifically, it acts as an antagonist of TGF-beta signalling, a pathway known to be relevant to colon cancer development.   

The authors suggest that the SMAD7 risk variants likely contribute to about 15% of colorectal cancer cases.  For those of us practicing clinical cancer genetics, however, it is important to note that SMAD7 seems to be involved in less than 1% of familial colon cancer though.  This fact, in conjunction with the relatively modest odds ratios, will likely limit applicability of this new result to the individual patient.  Nevertheless, I can certainly see a future coming in which the SMAD7 SNPs - presumably in conjunction with other colon cancer risk SNPs - are utilized on a population-wide basis to partition individuals into different risk categories with different recommended screening strategies.