Cancer and Your Genes

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.

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.

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.

 

Childhood Cancer and Birth Defects

It is now well known that certain clinical genetic syndromes recognized in childhood are associated with an increased risk of cancer development.  For example, in the Gorlin syndrome (also known as Nevoid Basal Cell Carcinoma Syndrome), which may affect ~1 in 40,000 individuals, a mutation in the PTCH gene leads to a number of unusual features including multiple jaw cysts, a very large head circumference, and prominent foreheads in addition to skeletal (bifid ribs and wedge-shaped vertebrae) and other anomalies.  Although the causative mutation in PTCH leads to these morphological abnormalities, it also leads to a substantial increase in cancer risk, primarily for skin basal cell carcinomas and medulloblastoma.

Although a number of studies have tried more broadly to assess the association between various birth defects (major malformations and minor anomalies) and cancer, these have been plagued by limitations including the reliance on chart reports of the morphological abnormalities.

A new study, reported in the January 2 issue of JAMA, provides an intriguing new look at this issue. 

The authors personally examined a total of 1073 childhood cancer patients and 1007 controls individuals (all patients and controls were of northern European descent) without cancer with an eye toward cataloging "morphological abnormalities" (both major birth defects and minor anomalies) in a standardized fashion.

Interestingly, they found that both major birth defects and minor anomalies were significantly more common in the pediatric cancer group as compared to controls.  For example, per 1000 individuals, 268 major abnormalities were found in cancer patients vs. 155 in controls; likewise, there were 1252 minor anomalies per 1000 individuals in cancer patients vs. 898 per 1000 controls.  This was statistically significant and is consistent with the notion that at least a subset of pediatric cancers are associated with genetic defects that might also predispose to combinations of birth defects and/or minor congenital anomalies. 

In 42 patients, there was an already established clinical genetic syndrome.  Even after these patients were removed from the analysis, there was still a significantly higher number of major abnormalities and minor anomalies in the cancer patients as compared to controls.

After excluding the 42 patients with preexisting diagnoses, the authors sought to assess which congenital anomalies seem to be particularly associated with pediatric cancer.  For example, they showed that blepharophimosis (a static reduction in the distance between the upper/lower eyelid resulting in a narrowed slit-like appearance), a minor anomaly, was about 11-times more likely to be found in pediatric cancer patients as compared to controls.  Some of the other abnormalities that were statistically associated with pediatric cancer were asymmetric lower limbs and broad feet (appearing disproportionately wide for length and for which the measured width is >95th percentile for age).

The authors then went on to make some initial attempts to identify patterns of morphological abnormalities to classify them into putative new syndromes.

Overall, this study is very intriguing, but has some methodological limitations that will require validation of the result in an independent group of patients and controls.  Nevertheless, this is a very plausible result supported by the existence of a number of known genetic syndromes in which certain birth defects cluster with certain types of cancer. 

This study provides a foundation on which future efforts to identify new tumor predisposition syndromes will be based.  Ultimately, this should allow improved efforts to screen for and/or prevent some childhood cancers.

Medicare and Genetic Testing for Cancer Risk

I just received a letter from Myriad Genetics regarding likely changes in the Medicare policy for reimbursement of genetic testing.  The letter summarizes a number of proposed changes to this policy which are likely to go into effect beginning Nov. 1. 

There's some good news here:

• Inclusion of criteria for testing of the MSH6 gene in Lynch syndrome (aka Hereditary Non-polyposis Colorectal Cancer [HNPCC] syndrome)
• In order for genetic testing to be reimbursed, documentation requirements will include an Informed Consent document that indicates that the patient has been informed of a number of specific issues and agrees to post-test counseling

There is some news that is perhaps not so good:

• There will be a clear-cut requirement that there be documentation in the medical record and/or office notes that the genetic testing is intended for the medical management of the patient (i.e., the patient sitting in front of the physician or genetic counselor, not their family members).  This is potentially bad news for those who feel strongly that genetic information has substantial value beyond that which immediately affects clinical care and decision-making.  However, it is not surprising given the enormous cost pressures on Medicare and the ways in which we fund and evaluate medical care currently in the U.S.
• Testing of unaffected (i.e., no personal history of cancer) individuals will not be covered.  This is potentially a big problem.  And many will argue that it is a misguided rule change.  Although the Medicare population is 65 and older and perhaps less likely to benefit from preventive options guided by genetic testing, this proposed change will negatively impact care of families guided by genetic testing in a very important way:

A common scenario in the cancer genetics clinic might involve a woman who is in her mid-30s and concerned about her risk for breast and ovarian cancer, because one of her paternal aunts died of premenopausal breast cancer and another of her father's sisters died of ovarian cancer diagnosed in her 40s.

A cardinal rule in clinical cancer genetics is that you always want to do the genetic test on someone in the family who has had a cancer diagnosis that is suspicious for the risk syndrome that you are considering.  If either of this woman's aunts were alive, they would clearly be the best people to test first. 

However, they both died of their disease.  In the absence of other individuals with cancer to test, the patient's healthy father would be the next best person to test.  The reasoning is as follows:

If we just test that woman in clinic for BRCA1 and BRCA2 mutations and the test is normal, we don't know whether this is because: 1) other family members have a detectable BRCA1 or BRCA2 mutation that she did not inherit (in this case, her cancer risk in the above scenario would be no different than that of any other woman) or 2) the early breast and ovarian cancer cases in the aunts might have occurred in the absence of any known BRCA1 and BRCA2 mutations (in this case, the test for the patient in clinic is not informative). 

If the patient's aunts had a BRCA1 or BRCA2 mutation, then there is a 50 percent chance that her father will have it as well.  Therefore, by testing him first, it can make the information gained by the patient's BRCA1 and BRCA2 testing more helpful.

As we move toward a future of more predictive and preventive medicine incorporating genetic/genomic information, there will continue to be tension at the intersection of the prevailing medical/reimbursement model that focuses on the patient and attempts to incorporate genetic information which is most often more valuable in the context of the whole family.  Ironically, to realize the full potential of personalized medicine, it will be essential to resolve these impediments to care of the whole family.

Cancer and Your Genes

Welcome to my new blog, "Cancer and Your Genes."  I'm also the author of "DNA and You" - a personalized genomics focused blog located here. 

As a clinical cancer geneticist (with board certification in both clinical genetics and internal medicine), I have become more interested in creative means to educate the public about the contribution that our genes make to cancer risk.  I intend for this to be a dialogue and aspire to present solid, well-reasoned, and, hopefully, interesting discussion of important emerging issues in this area. 

It's important to point out that the information presented here does not substitute for care from your personal physician.  Likewise, reading this blog does not constitute the establishment of a physician-patient relationship between us.  If you would like more information, I would encourage you to schedule an appointment to see a clinical geneticist or genetic counselor in your area.  A good place to find a genetic services provider in your area is the Clinic Directory at the GeneTests website.

In any event, I hope that you both enjoy this blog and find the information useful.