Cancer and Your Genes

Breast Cancer Gene Patenting Lawsuit Pitting ACLU, ACMG and Others Against Myriad Genetics and University of Utah Research Foundation Will Continue

A judge refused to throw out the lawsuit which could plausibly have broad implications for gene patenting, but seems more likely to be posturing to encourage a political/legislative solution.  Ars Technica has excellent coverage here.

Christina Applegate Talks About Her Breast Cancer Surgery on Oprah Today

According to the show's website, Christina Applegate will be appearing on Oprah today:

"Christina Applegate opens up about her battle with cancer and her radical decision to remove both breasts.  Then, we all have so many questions.  What should we be doing?"

Apparently, Ms. Applegate will be discussing her breast cancer diagnosis and the genetic testing that apparently led to her decision to pursue bilateral mastectomy recently.

A YouTube preview of the show is located here.

NY Times Article on Sunscreens for Those Interested in Prevention of Melanoma and Other Skin Cancers

If you have a family history of melanoma or are just interested in doing everything you can to prevent skin cancer, you may be interested in this article by Tara Parker-Pope at the NY Times.

Tony Snow, Former Bush Press Secretary, Dies at 53: A Reminder About Familial Colon Cancer and Opportunities for Prevention

Tony Snow, the conservative writer, commentator, and former Bush administration Press Secretary, died on the morning of July 12 at the age of 53 of colorectal cancer. 

It's worth mentioning that Mr. Snow had a family history of colon cancer, as his mother apparently died of the disease when he was 17 years old.  As Mr. Snow has publicly acknowledged a diagnosis of ulcerative colitis (UC), it seems most likely that the cancer in his family is related to UC, rather than to what are arguably the two most important hereditary cancer predisposition syndromes for colon cancer, Lynch syndrome (aka hereditary non-polyposis colorectal cancer or HNPCC) and familial adenomatous polyposis (FAP).

The lifetime risk for colon cancer in individuals at average risk in the United States is about 5 percent.  Nine out of ten cases occur after the age of 50.  Individuals with ulcerative colitis have a ~3- to 12-fold elevated risk of developing colon cancer depending on the extent of colon involvement and the length of time the disease has been present.  Ulcerative colitis risk is influenced by genetics, but the inheritance is complex, without major deterministic susceptibility genes like those for FAP (APC) and Lynch syndrome (MLH1, MSH2, MSH6, PMS2). 

Mr. Snow's death is an opportunity to remind folks that colon cancer, in general, is a highly preventable disease.  Stay tuned to future posts for more details.

Brewing Turf War Between Breast Surgeons and Plastic Surgeons Over Breast Reconstruction

The Wall Street Journal Health Blog has an interesting story on a brewing turf war between breast surgeons and plastic surgeons over breast reconstruction procedures.

Some women with breast cancer - including some with BRCA1 or BRCA2 mutations undergoing bilateral mastectomy - decide to have breast reconstruction performed.  This procedure has generally been performed by a plastic surgeon in a separate procedure from the mastectomy itself.  Now, as noted by the WSJ, a growing number of breast surgeons (without plastics training) are learning the breast reconstruction procedures and beginning to offer it at the same time as the mastectomy itself. 

Undoubtedly, this will lead to some turf wars.  If you are shopping around for a breast reconstruction surgeon, the most important question to ask is how many breast reconstruction procedures have they done...

Poetry and Art as Outlets for Cancer Patients

Tara Parker-Pope at the Well blog (NY Times) has an interesting post on poetry as an expressive outlet for cancer patients. 

Other forms of art can also be helpful (see here):

• Confronting Cancer Through Art
• Art for Recovery
• Joan Bowman
• The Art Therapy Blog
• Strength from Unity
• Arts in Medicine Program

Where You Get Your Mammogram Matters!

A research group led by Dr. Stephen Taplin of the National Cancer Institute has published a paper in the June 18th issue of the Journal of the National Cancer Institute that assesses whether certain factors differing between mammography facilities are associated with better interpretive accuracy on screening mammograms.

The bottom line is that there are several things that were signficant.  Sensitivity, the ability to detect breast cancers, was quite high and varied little.  However, specificity and positive predictive value varied significantly between sites.  Thus, it seems that the degree to which sites may be "overcalling" their reads (presumably to avoid missing something) varies. 

The following mammography facility traits were associated with better interpretive accuracy for screening mammography:

• Performing only screening mammography at the facility (as opposed to screening plus diagnostic mammography)
• Having a breast imaging specialist interpreting the mammograms
• Not performing double reading of mammograms (more false positives when read by more than one radiologist)
• Conducted audit reviews 2 or more times per year (where individual radiologist-level performance data is shared with the radiologist)

The authors note that it was surprising that double reading did not improve overall test accuracy and that this contrasts with the results of randomized clinical trials.  It may be that double reading methods differ or have been implemented differently in typical clinical practice environments outside of clinical trials.  This deserves a closer look in the future.  Given the relatively weak effect of this predictor of performance, the authors suggested that it should not be utilized to differentiate amongst facility performance until further detailed research is done to sort out the controversy.

It is important to keep in mind that the above factors affected specificity and positive-predictive value primarily.  The authors point out that whether sensitivity or specificity is most important in picking a mammogram facility is dependent on a value judgment.  That is, some women may be most concerned about sensitivity at all costs (i.e., a higher false positive rate leading to a biopsy does not matter).  Other women may wish to consider factors like those noted above that affect specificity and positive predictive value (i.e., they would like to avoid unnecessary biopsies while keeping sensitivity high). 

The results of this retrospective study should be confirmed elsewhere before they are utilized for decision-making.  Nevertheless, you may want to have a dialogue with your physician about mammography facility choice.

Snake Oil Alert: Blue Light Cancer Treatment at ThinkGene

Here's a post from Josh Hill at ThinkGene about an unpublished study of Blue Light effect on tumors in mice.  It's a hands-down winner of today's Snake Oil of the Day Award.  Lest we give cancer patients and the general public false hope and the wrong impression, it might be wise to let one like this at least get through peer review before sensationalizing it...

Survival in Prostate Cancer: It May Be Affected By Your Genes

We frequently hear about connections between our genes and the risk of developing prostate and other cancers.  However, a new study provides further evidence in support of an old idea that our genes may affect something much more important than the development of cancer; indeed, this new research supports the concept that our genes affect survival from prostate cancer. 

Dr. Kari Hemminki and colleagues, in a fascinating piece of epidemiologic sleuthing published in the Journal of Clinical Oncology, utilized the Swedish Family-Cancer Database to determine whether survival patterns from prostate cancer clustered within families.  By assessing survival data for more than 600 prostate cancer-affected sons and their fathers (who also had prostate cancer), they were able to show that sons of fathers with shorter survival from prostate cancer tended to survive for a shorter period as well.  Likewise, sons of fathers who survived for a longer period of time after the diagnosis tended to survive for a longer period of time as well. 

Although these results shouldn't be utilized at this point to guide treatment decisions, as they may be subject to some biases and need further confirmation, they should pave the way for future studies aimed at identification of genes underlying this familial risk.  This would be a refreshing approach in an area of medicine beset with substantial uncertainty surrounding best treatments - particularly with respect to decisions regarding prostatectomy versus "watchful waiting."  It will be very interesting to see how this turns out, and it is important to remember that genes that may confer risk of metastatic disease and/or poor survival may not be genes that are involved in risk of developing prostate cancer (i.e., they only affect the rate of progression or metastasis of the disease once it is already established). 

Selected References

K Hemminki et al.  Concordance of survival in family members with prostate cancer.  Journal of Clinical Oncology 26: 1705-9, 2008.

Resources

Prostate Cancer Foundation

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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.