Cancer and Your Genes

Other Cancers Seen in Families with RAD51D Mutations

Two days ago, we discussed a recent study by Dr. Nazneen Rahman and colleagues which clearly demonstrated that inherited mutations in a gene called RAD51D result in a substantial elevation in risk for ovarian cancer.  Some families with mutations in the study also had some other cancer types in the family tree.  So, does this mean that the other cancer types in these families are also due to the RAD51D mutations?

In short, the answer is that we don't know.  Ovarian cancer risk was the only one that Dr. Rahman and her colleagues could pin down as being associated with RAD51D mutations with any statistical confidence.  For the others, future studies can address the specific question; however, they may be challenging and require extremely large sample sizes in order to have the statistical power to answer the question.

Here are the other cancer types that were seen in the eight families with inactivating RAD51D mutations in the study:

Breast Cancer

•  Seen in 8 out of 8 families (not surprising given that the families were included in the study because they had both ovarian and breast cancer)
• There were 13 breast cancer cases total in these 8 families
• Two of the breast cancer cases were bilateral
• Seven of the 13 cases were found to have inactivating RAD51D mutations (the other 6 were not tested)
• In contrast to ovarian cancer, the association of RAD51D mutations with breast cancer was not statistically significant (Relative Risk = 1.32 with 95% confidence intervals from 0.59 - 2.96)

Colorectal Cancer

•  Seen in 5 out of 8 families (keep in mind that some of these extended families are quite large and that colorectal cancer is common)
• There were 8 total colorectal cancer cases in the 5 families
• None of the affected individuals were tested for the presence of mutations in this study

Lung Cancer

•  Seen in 1 individual in 1 out of 8 families (keep in mind that some of these extended families are quite large and that lung cancer is common)
• The individual with lung cancer was not tested for the presence of the familial RAD51D mutation in this study

Non-Hodgkin Lymphoma

•  Seen in 1 individual in 1 out of 8 families
• The individual with NHL was not tested for the presence of the familial RAD51D mutation

Pancreatic Cancer

•  Seen in 2 individuals total from 2 out of 8 families
• The 2 individuals with pancreatic cancer were not tested for the familial RAD51D mutation

Prostate Cancer

• A total of 2 cases were seen in 1 out of the 8 families
• The 2 individuals with prostate cancer were not tested for the familial RAD51D mutation

It's very important to keep in mind that seeing these cancers in these families could just be due to chance or to the fact that the families were more likely to come to the researchers' attention because of the other cancers (particularly breast cancer).  Thus, we can't say anything about whether RAD51D mutations may lead to elevated risk for any cancer other than ovarian cancer based on this study.  Nevertheless, it will be important in the future to keep an eye on this. 

Bottom Line Implications

1. Mutations in the RAD51D gene lead to ovarian cancer risk in some families in which the familial ovarian cancer risk is not explained by mutations in BRCA1/2

2. Although several other cancer types (including breast cancer) were seen in the families with mutations, there was no statistically significant evidence from this study implicating RAD51D mutations in risk for any of the other cancer types. 

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Selected References

Loveday C, Turnbull C, Ramsay E, et al.  Germline mutations in RAD51D confer susceptibility to ovarian cancer.  Nature Genetics 2011 (Published online August 7 2011)

Family History of Cancer Changes Over Time: Why You Need to Keep Your Primary Care Doctor Updated

If you are interested in cancer prevention, you may know that for common cancers family history is one of the most important and useful tools that we have to identify people at elevated risk (who are likely to benefit most from more intensive screening and/or preventative measures).

Despite this fact, discussion of family history often gets lost in the shuffle in primary care - which is not surprising given how much stuff today's healthcare providers need to pack into a visit that often may only last 10 minutes or so.   That said, many healthcare providers are doing a better job of asking about a family history of cancer, but it is usually a static, one-time assessment that may happen most at the time of initiation of primary care with a new doctor.

A newly published research article by Argyrios Ziogas, Nora Horick, Sharon Plon, Dianne Finkelstein and colleagues from the Cancer Genetics Network (CGN) in JAMA provides evidence and analysis that suggests that doctors and patients should also pay more attention to changes in family history of cancer over time.

Ziogas and colleagues used a couple of different analytical approaches to try to find answers to this question:

How often do family cancer histories change enough over time that they would merit changes in the intensity of screening based on American Cancer Society guidelines?

They focused on 3 of the most common cancer types: breast cancer, colorectal cancer, and prostate cancer.  Although there are a few caveats, in general, their results suggest that it is well worth it for people to make sure that their doctors are aware of any changes in their cancer history.

In the case of breast cancer, their results suggest that about 4 percent of women will have a change in their family history of cancer between the ages of 30 and 50 sufficient to suggest that they are in a somewhat higher risk group that may benefit from breast MRI screening (per American Cancer Society Guidelines). 

For colorectal cancer, their results suggest that about 5 percent of people will have a change in their family history of cancer between ages 30 and 50 that suggests that a more aggressive colonoscopy screening strategy may be warranted (per American Cancer Society Guidelines).

The impact of prostate cancer family history changes was less impressive. 

Overall, it seems clear that in the clinic we need to think of cancer family history as the often changing entity that it is, rather than the static, never changing, thing that may get entered in the clinic chart at the first visit and then never re-visited.

 What You Can Do: If someone in your family is newly diagnosed with cancer (parents, brothers, sisters, children, aunts, uncles, grandparents, cousins), let your physicians and other healthcare providers know about it the next time you see them.  This way, they can update the family history that they have on file for you and consider whether the information might suggest that you should have more intensive cancer screening.

Cited Reference

Ziogas A, Horick NK, Kinney AY, et al.  Clinically relevant changes in family history of cancer over time.  JAMA 2011; 306:172-8. 

Further Reading

Acheson LS.  Recording, interpreting, and updating the family history of cancer: implications for cancer prevention.  JAMA 2011; 306:208-10.

Qureshi N, Wilson B, Santaguida P, et al.  Collection and use of cancer family history in primary care: Evidence Report/Technology Assessment No. 159.  Rockville, MD: Agency for Healthcare Research and Quality, 2007.  AHRQ Publication 08-E001.

Scheuner MT, McNeel TS, Freedman AN.  Population prevalence of familial cancer and common hereditary cancer syndromes: the 2005 California Health Interview Survey.  Genet Med 2010; 12:726-35.

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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.

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.