DNA and You

Genetic Voyeurism on TV

A colleague just pointed out a fairly astonishing occurrence on the Today Show this week.  On Tuesday, a story ran in the Jackson, Mississippi Clarion Ledger about Carla Tigner - who has both a personal and family history of breast cancer.  Her father, Paul Ott Carruth (a Mississippi conservationist, entertainer, and talk-show host), apparently was diagnosed with breast cancer in May.  Ms. Tigner was also diagnosed with breast cancer in 2005 at age 42 and chose to undergo a bilateral mastectomy given her mother's history of ovarian cancer (according to this story published in the Daily Leader).  Ms. Tigner has two minor children, including a 16-year-old daughter.

In what one Today producer called, "must-see television," Tigner announced her BRCA testing results to the world on the Today Show on Thursday morning, apparently shortly after receiving them by phone from her oncologist, Dr. Grace Shumaker.  (I did not see the show, but there is a description of what transpired published here.)  Apparently, she does not have her father's BRCA2 mutation.

Pointing to continued confusion in the press about the nature of the genetic changes in the BRCA1 and BRCA2 genes that lead to breast cancer risk, one news report when implying that Mr. Carruth has a BRCA2 mutation states that, "Carruth's tests showed he is a carrier of the BRCA 2 [sic] gene."  Of course we all "carry" the BRCA2 gene - in fact we each have two copies of the BRCA2 gene.  Presumably they meant to say that Carruth's test showed that he has a mutation in - one of his copies of - the BRCA2 gene. 

Although a published report suggests that Carruth and Tigner were put in touch with the Today Show by a local television journalist, it is interesting that this comes in the midst of a direct-to-consumer advertising blitz by the company that performs clinical BRCA1 and BRCA2 testing in the U.S., Myriad Genetics.  The direct-to-consumer approach has been extremely controversial (see NY Times article here).  Although it appears the company had nothing to do with the Today Show appearance of Ms. Tigner (aside from performing the testing as ordered by Dr. Shumaker),  Myriad couldn't possibly buy better advertising.

Given Ms. Tigner's mother's reported ovarian cancer (which occurred at an early age), this case typifies the complexity of family history that is best dealt with by extensive pre- and post-test counseling, which may be difficult to obtain in some of the testing instances prompted by the direct-to-consumer advertising campaign.  For example, it is impossible to decipher from the above referenced news reports whether Ms. Tigner was tested for: 1) only the presence or absence of the specific known BRCA2 mutation found in her father or 2) all detectable BRCA2 and BRCA1 mutations in the comprehensive testing options from Myriad Genetics.  If the former were true, then it would be irresponsible to tell Ms. Tigner that she can completely breathe a sigh of relief (particularly if she still retains her ovaries and fallopian tubes); although inheritance of her father's BRCA2 mutation would have been ruled out, she could still be at risk of inheriting a BRCA1 or BRCA2 mutation from her mother, who suspiciously died of early ovarian cancer.  If the latter were the case, it would be important to tell Ms. Tigner that although the comprehensive testing option for the BRCA1 and BRCA2 genes is a very good test, there remains a small residual risk that she could have inherited from her mother a genetic change not detectable with the current testing technology, which could have substantial implications for breast and ovarian cancer risk.  In other words, we would not be able to distinguish between two possibilities: 1) her mother's ovarian cancer was related to a BRCA1 or BRCA2 mutation which Ms. Tigner did not inherit or 2) her mother had early-onset ovarian cancer in the context of no detectable BRCA1 or BRCA2 mutation.  In this second case, Ms. Tigner may have some residual risk for ovarian cancer (she has already had a bilateral mastectomy), because her mother's ovarian cancer might have been due to either a change affecting the BRCA1 or BRCA2 genes that is not detectable with current testing technology, or it could be due to other genetic factors that physicians and scientists do not understand yet. 

More concerning to me though is the fact that a mother would agree to broadcast her results for a genetic test for a highly-penetrant breast and ovarian cancer predisposition syndrome to the world, knowing that - if she has a mutation - her minor children could have a 50% chance of being in the same boat.  In other words, this is very different from having a colonoscopy on morning television; in this case with the genetic testing results, the world had the potential to learn information about other individuals - Tigner's children who are minors - that could have implications for future insurability, potential stigmatization, and maybe even dating prospects.  As a clinical geneticist, I fully recognize that individual families have to figure out how to deal with genetic information relevant to health in their own way.  And in this case, I'm glad that there is open discussion in this family.  Nevertheless, we all need to think carefully and wisely about what information we want to share with the entire world and what information might be best shared only with family members, trusted friends, physicians (including clinical cancer geneticists), and other genetics professionals (like genetic counselors). 

New Blog: Cancer and Your Genes

I've started another blog, "Cancer and Your Genes," which can be found here.  It will be focused on the intersection of our genomes and cancer risk, with particular emphasis on educating the lay public about genetic risks for cancer.

Mountains Out of Molehills? Or the Real Deal?

Despite some significant challenges in bringing effective personalized medicine approaches to the clinic, cancer treatment is one area in which personalized medicine and molecularly-targeted therapies have begun to come to fruition already.  In addition to Gleevec, which effectively targets the BCR-ABL fusion protein that is characteristic of chronic myelogenous leukemia (CML) in humans, Herceptin is important in the treatment of the subset of breast cancer patients whose cancers have substantial expression of the "Her2/Neu" protein.

However, these molecularly targeted therapies that focus on specific proteins important to the causation and maintenance of a subset of cancer cases are only available for a small percentage of all cancers.  To move closer to truly targeted therapy (which hopefully would have less severe side effects than current approaches with relatively non-specific cytotoxic drugs and radiation), we must know more about the relatively complicated changes in the DNA of the cancer cell.

Although it frequently seems like the more we learn about cancer the more complex the problem becomes, a paper published in the online edition of Science today makes a significant contribution to our knowledge of what goes awry in the development of breast and colon cancers.  (Although the full paper is available only by subscription, there is a press release with more information about the findings at the HHMI website) 

In this work, groups led by Giovanni Parmigiani, Kenneth Kinzler, Victor Velculescu, and Bert Vogelstein utilized a high-throughput DNA sequencing approach to look at the coding sequences (the DNA sequence coding for protein sequence) of more than 18,000 genes in each of 11 different breast cancer cases and 11 colon cancer cases.  Utilizing a careful approach to determine that mutations occurred somatically in the development of the cancer (as opposed to being polymorphisms present in all of the DNA of the individual at birth), the study basically showed that an impressively high percentage of the genes had a non-silent mutation (i.e., one that altered the protein coding sequence) in at least 1 cancer case: 9.4% of the total number of genes analyzed.  Putative cancer-related genes were evaluated in another set of cancers.  There were a total of 280 genes (equally distributed between breast and colon cancers) in all that were validated by the presence of mutations in both the initial cancer set and the validation tumor set.  Further analyses were performed to assess the plausibility that these genes were mutated more often in the cancers than would be predicted by chance. 

Although it is not news that cancer is a genetic disease associated with the accumulation of mutations in several key genes (that presumably differ by tumor/tissue type), the high-throughput resequencing approach utilized in this work suggests much more complexity in the mutated cancer genome than was previously recognized.  By plotting a score related to gene mutation frequency for each gene on something resembling a topographical map, the authors point out that while there are certainly still several "mountains" that appear to likely to be very important in cancer development, perhaps the more striking feature is an extremely high number of "hills" (genes mutated at a much lower frequency in a given cancer type, but which still likely play a role in causation or maintenance). 

Although some may suggest that the authors are making mountains out of molehills, I believe that their interpretation is likely correct.  The ability to sequence virtually the entire coding genome of a tumor is very exciting; with the coming drop in sequencing costs, this could be more realistically applied to individual patient tumors in a clinical context.  The hard part will be devising strategies to act on this information in a way that improves clinical outcomes.  However, as the authors suggest, many of the "hills" can be grouped into one of a small number of biochemical pathways.  Future studies will no doubt assess whether drugs targeting these pathways can be applied on a rational basis based on high-throughput sequencing of patient tumor DNA. 

Despite some significant challenges in bringing effective personalized medicine approaches to the clinic, cancer treatment is one area in which personalized medicine and molecularly-targeted therapies have begun to come to fruition already.  In addition to Gleevec, which effectively targets the BCR-ABL fusion protein that is characteristic of chronic myelogenous leukemia (CML) in humans, Herceptin is important in the treatment of the subset of breast cancer patients whose cancers have substantial expression of the "Her2/Neu" protein.

However, these molecularly targeted therapies that focus on specific proteins important to the causation and maintenance of a subset of cancer cases are only available for a small percentage of all cancers.  To move closer to truly targeted therapy (which hopefully would have less severe side effects than current approaches with relatively non-specific cytotoxic drugs and radiation), we must know more about the relatively complicated changes in the DNA of the cancer cell.

Although it frequently seems like the more we learn about cancer the more complex the problem becomes, a paper published in the online edition of Science today makes a significant contribution to our knowledge of what goes awry in the development of breast and colon cancers.  (Although the full paper is available only by subscription, there is a press release with more information about the findings at the HHMI website) 

In this work, groups led by Giovanni Parmigiani, Kenneth Kinzler, Victor Velculescu, and Bert Vogelstein utilized a high-throughput DNA sequencing approach to look at the coding sequences (the DNA sequence coding for protein sequence) of more than 18,000 genes in each of 11 different breast cancer cases and 11 colon cancer cases.  Utilizing a careful approach to determine that mutations occurred somatically in the development of the cancer (as opposed to being polymorphisms present in all of the DNA of the individual at birth), the study basically showed that an impressively high percentage of the genes had a non-silent mutation (i.e., one that altered the protein coding sequence) in at least 1 cancer case: 9.4% of the total number of genes analyzed.  Putative cancer-related genes were evaluated in another set of cancers.  There were a total of 280 genes (equally distributed between breast and colon cancers) in all that were validated by the presence of mutations in both the initial cancer set and the validation tumor set.  Further analyses were performed to assess the plausibility that these genes were mutated more often in the cancers than would be predicted by chance. 

Although it is not news that cancer is a genetic disease associated with the accumulation of mutations in several key genes (that presumably differ by tumor/tissue type), the high-throughput resequencing approach utilized in this work suggests much more complexity in the mutated cancer genome than was previously recognized.  By plotting a score related to gene mutation frequency for each gene on something resembling a topographical map, the authors point out that while there are certainly still several "mountains" that appear to likely to be very important in cancer development, perhaps the more striking feature is an extremely high number of "hills" (genes mutated at a much lower frequency in a given cancer type, but which still likely play a role in causation or maintenance). 

Although some may suggest that the authors are making mountains out of molehills, I believe that their interpretation is likely correct.  The ability to sequence virtually the entire coding genome of a tumor is very exciting; with the coming drop in sequencing costs, this could be more realistically applied to individual patient tumors in a clinical context.  The hard part will be devising strategies to act on this information in a way that improves clinical outcomes.  However, as the authors suggest, many of the "hills" can be grouped into one of a small number of biochemical pathways.  Future studies will no doubt assess whether drugs targeting these pathways can be applied on a rational basis based on high-throughput sequencing of patient tumor DNA.