This week in NEJM

So I have been reading about how the new article in the New England Journal of Medicine shows that BRCA gene mutations are not worse than sporadic breast cancers due to non-BRCA mutations.

If you look at the article you will see that there are many reasons why this is flawed thinking. But more importnatly it flies in the face of another study which actually showed and increased risk in worse outcomes with BRCA1 mutations.

So on closer inspection what was the NEJM article about?

They took all breast cancer specimens available in Israel's National Healthcare repository and looked for 3 I repeat 3 FOUNDER MUTATIONS....... This immediately makes the study invalid to comparison on women who have non ashkenazi mutations, especially if they are not founder mutations.

Secondly they analyzed outcomes retrospectively. This is a notorious way to get confounding results as well.

Thirdly this study did not have interpretable data regarding estrogen or progesterone receptor status.......This is a big deal!!!

And Lastly,
"We had 16-year follow-up data on mortality and incident cancers, but information on the cause of death was available from the Central Bureau of Statistics only for deaths that occurred before 2000." None from after 2000........

The Gene Sherpa Says: Before bloggers and press go off half cocked in this interpretation we need to be careful in how we evaluate this study. This ONLY means if you are an ashkenazi jew from Israeli heritage and have one of 3 founder mutations, then you are not more likely to have adverse outcomes than ANYONE else who is Israeli and Ashkenazi with non founder mutation breast cancer....That's IT. Nothing else can be extrapolated here. To those who are.....tread carefully...Because you are misleading the public!

Chemotherapy Toxicity Genes

Imagine if you could predict who would get the nasty side effects of chemotherapy before giving it. We could then taper the chemotherapy giving less of a dose and achieve the same response. Well, the first part of that dream is here today. At St Jude Children's Research Hospital they have been actively investigating pharmacogenomics and chemotherapy. In a study to be released in the May 15th edition of Blood we have just that.

The major findings include

• During the induction phase Vitamin D Receptor polymorphisms were linked with gastrointesinal symptoms (diarrhea, nausea, vomiting) 6.85 times more likely.
• Polymorphisms in Cytochrome p450-Family 3-subfamily A-number 5, were almost 5 times more likely to have infections and Neurotoxicity
• During consolidation phase the Reduce Folate Carrier polymorphism led to the GI side effects with a 10.4 odds ratio.
• UGT1a1 polymorphisms led to jaundice as well as reduced clearance of an agent called methotrexate (a chemo drug) perhaps leading to increased toxicity as well

This is a major study, that has had some replication in one gene or another. But the compiling of these polymorphisms has not been done. Likely we will need one more round of evaluation. But after that...we could have a pharmacogenomic test for side effects.

The Gene Sherpa says: This is great, but how do we adjust the chemo to avoid these reactions. We will likely need an adjustment scale based on polymorphisms. AKA Personalized Medicine! I am certain St Jude's has this in the works. Let's keep our eyes peeled :)

Is nutrigenomics ready for prime time???

In May's edition of the American Journal of Human Genetics there is an article positing researching whether polymorphisms in MTHFR affect homocysteine/folate/one carbon metabolism. If so, does vitamin status play a role. B vitamins are essential for the remethylation and transsulfuration of homocysteine, which is an important intermediate in one-carbon metabolism.
What they found is that persons with a polymorphism in the MTHFR (I know what you are thinking....sounds like) namely the change at base 677 from a C to a T, had difficulties with this metabolism when low on B vitamins.
So is Nutrigenomics here? You know, the right vitamin for the right person at the right time...
Not so fast.

1. Homocysteine is only poorly linked to heart disease in asymptomatic patients
2. There is some literature which states that B vitamin supplementation in patients with prior heart attack can cause WORSE outcomes.
3. This is a replicated study, but not on a heterogeneous population...........

All things considered I would do 3 things.

1. Continue with my multivitamin
2. Only supplement with B vitamins if I have NOT had a heart attack
3. Go over the results of any Nutrigenomic test I took with a geneticist