Monday, August 18, 2008

The New BRCA....this time its the Colon!!!

This is a fantastic review. I have been very careful trying to avoid hyping tests. I do this because we need validation and some evidence for use would be nice. The problem is that sometimes a test is so powerful that it should not be sat on.

This was the case with the BRCA genes. Even in 1996 Francis Collins was warning about testing without really thinking out the consequences. From his 1996 article in the New England Journal of Medicine.

The benefits of presymptomatic testing to determine susceptibility to common cancers such as those of the breast, ovary, colon, and prostate are potentially substantial. Nonetheless, it is critical that we create safeguards to ensure that the benefits of testing exceed the risks. The technical ability to perform tests for mutations should not be confused with a mandate to offer them. In the long run, the identification of BRCA1 and other cancer-susceptibility genes should permit the development of new and more effective therapies, so that physicians can not only predict future risks, but also reduce those risks reliably and safely before disease occurs.

I say this because we now have evidence of what I would term a genetic risk factor akin to BRCA1.

Recently published and talked about on Think Gene.....

Why do I say this is the next BRCA and may be even bigger?
New cases of colorectal cancer in the US in 2007: 148, 810
Deaths: 49, 960
How does this line up with Breast Cancer? New cases 182,000. Deaths 41,000

Pretty similar. What percentage of Breast Cancer is "hereditary" approximately 7-10 percent.
BRCA, we think accounts for a significant amount of this.

Colon Cancer? Way more....maybe up to 40% are familial.....but due to a specific gene? Far less 5%...until now.
You see, having a family member with colorectal cancer puts your risk up 400% from the general population. Even having polyps in the family increases your risk.

With that in mind, this study:
Was just published in Science. What is bad about print journals???? This was submitted in April....they (the researchers) have been sitting on this.....and likely creating a clinical test.

What did they find?

Conservative estimates suggest that ASE confers a substantially increased risk of CRC (odds ratio 8.7; 95% confidence interval: 2.6 to 29.1), but these estimates require confirmation and likely will show ethnic differences.

This was a surprise for some, but we had seen hints of this in JAMA. It turns out they estimate 20% maybe up to 30% of familial colorectal cancers have issues with reduced expression of the TGFB receptor subtype 1. This is due to a specific mutations which can be tested for in research and may soon be clinically available at Helix Health of Connecticut and other genetic providers. 30% of 30% of 148,000 per year!!!!! That is 15,000 people who will potentially positive.......that's just the afflicted members not even their family members in the US! This is a much larger number than breast cancer.
I was speaking with a Venture Capital firm this week when a really smart VC partner asked can you project testing to reach this level in 3 years when the current data show a much smaller number? I answered him with this. We are finding new genetic risks that affect a much larger population. This is disruptive technology that could reach not only the small amount of rare diseases that exist today. We are talking testing that would benefit the over 300 million persons in the US. Now that is rapid growth! Tests like this are those harbingers..
So with that being said, some caveats:

1. This is only in caucasians....replication is needed for other ethnicities
2. Clinical testing is not YET available
3. No screening protocols have been clinically defined yet. BRCA took 10 years to have most of the kinks worked out. I am certain the public won't tolerate that long for this test. But it may need a few years of study....
The Sherpa Says:
An odds ratio of 8.7 for developing colorectal cancer in carriers of these alleles is a huge risk akin to the BRCAs. Even more impressive is that this could affect WAY more patients than the BRCAs. So I say, let's start studying this clinically and launch the test as soon as we have a good screening strategy!!!


cariaso said...

Customers of deCODEme and Navigenics seem to have already been tested for this. You can see this in the footer at
rs334348 that it occurs on the deCODEme Illumina Human 1M microarray. or on rs334349 for the Affy/Navigenics platforms.

Steve Murphy MD said...

I would be interested to see how they were reporting this risk. I think you need some family history context too. Cariaso, this is medicine IMHO......


Anonymous said...

From the deCodeMe website:

"A fraction (~5%) of colorectal cancer cases occur in families with multiple cases of the disease. An example of such a condition is multiple polyposis of the colon, where the inner surface of the colon is covered with thousands of polyps . In some instances, these cases are known to be caused by specific mutations in genes that substantially increase the risk of the disease. Individuals belonging to such families should seek counselling about preventive measures. Please note that the deCODEme Genetic Scan does not identify such rare and highly familial cancer genes, including APC, MLH1, MSH2, MSH6, and PMS2.

To date, six common genetic variants have been found that increase the risk of developing colorectal cancer. These variants are located in the SMAD7 gene on chromosome 18, in the CRAC1 gene on chromosome 15, 2 variants on chromosome 8 (one in the EIF3H gene and the other close to POU5F1P1) and variants on chromosomes 10 and 11."

Steve Murphy MD said...

First off,
The site is dead wrong. Most single gene causes for colorectal cancer.....PRIOR to this discovery were responsible for rare genetic syndrome predisposing or causing colorectal cancer. That number is 5-10%. They also forgot to mention the other genes responsible....

Second off,
Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) is not only colorectal cancer, and deCode should have that on their site.

This is why we need genetcists and counselors. THey are responsible for following up with patients when new things come out. BTW, according to Cariaso, the deCode and Navigenics chips have these polymorphisms. I wonder if you received any pretest counseling prior to that?

This is why we need person to person services, to talk about conditions and clarify confusion.


Berci Meskó said...

I'm always amazed how deeply you can analyze such a review. Nice post again, Steve!

Steve Murphy MD said...

Thanks Berci,
Glad you liked it!