Tip60 tips off breast cancer aggresiveness

According to a study published today in the journal Nature shows that a gene called Tip60 is involved in the development of breast cancer. But more importantly.........reduced expression of Tip60 protein leads to more aggressive tumors. Tip60 is a tumor suppressor gene unlike others.....

Let me explain. Usually you are required to have both copies of a tumor suppressor gene affected to start developing tumors. I feel that this theory along with all things mendelian will start to fade away. Why? Because we are much more complicated that punnet squares. The field of systems biology is growing and we will soon realize that we are a complex interactome, not just autosomal/Xlinked/Ylinked dominant/recessive genes.

So where were we? Well it turns out that this tumor suppressor gene only needs one copy malfunctioning to start enhancing tumor growth

From the Primary Investigator Dr Tim Crook "More aggressive types of breast cancers tend to recur after treatment, spread to other parts of the body and respond less well to chemotherapy. The identification of Tip60's role in breast cancer is a step towards predicting the aggressiveness of the disease and then individualising chemotherapy for women. If we can transfer this knowledge to the clinic, it could have dramatic effects."

From the Study

* Activity of the Tip60 gene was found to be lower in nearly half of all ductal breast cancers studied (21 of 52 cases) and in 17 out of 20 of tumours classed as 'high grade'

* The amount of TIP60 protein was studied in an additional 179 breast cancer samples. In almost three quarters of these (129/179), there was no TIP60 protein present in the cells' nucleus - in healthy cells this is where most of it is located. The proportion of cancers lacking nuclear TIP60 was even higher when they singled-out aggressive cancers and early cancers - suggesting that this is an early event in breast cancer development.

The Sherpa Says: Personalized medicine is coming and in many cases it is already here. This is an example of tumor tissue sampling to analyze outcomes. What is truly needed is a tissue bank that can put phenotype with genotype. Then we can have an excellent expression array analysis combined with phenotypic markers. This is the best way to put together personalized oncology. Trust me it is coming. Soon.....

What good is a map?

Imagine being stranded on a raft......An object is floating in the water. You paddle hard to get it. Once you do, you realize its a map. Hooray, you can finally find some land. Or can you?

There are some significant questions to ask yourself prior to having any utility gained from that map.

1. Can you read the map? I used to be in the Navy. We learned how to read nautical maps. But my father, a retired colonel in the Army, would have no clue where to begin. Imagine someone who had no training......


2. Where are you on that map? If you have no orientation, how could you hope to navigate. Where does the sun rise? Simple question. However, when asked almost 15% of Americans do not know the answer.


3. What is on the land you will be paddling to? If you paddle hard to get there only to find out that there are man eating natives, how good was your choice? Did you really want to find that land?

A map of your personal genome is much the same. Jason Bobe over at the Personal Genome comments on some of these topics. Who should be able to read the map? Should everyone have a Tom-Tom or Garmin? Should there be age limits on querying ability. And what if we find out something we didn't want to know? These are serious questions.

The Sherpa Says:

There will soon be a personal genome option. Everyone will be able to have an economically priced copy. We need some guidance on its interpretation. Personally, computers can only do so much. With all apologies to my colleauge Tim Arimond, we cannot program our way out of needing human interpretation. A computer cannot tell when you are scared, confused, upset......yet. I think that personal genome sequencing holds tremendous promise.........But it is only a map.

No More Skin Biopsies????

Imagine going to your dermatologists office and instead of getting biopsied for your funny looking mole, the dermatologist places a little sticker on the mark.

He sends it off in the mail and later that week you are told that it is just a mole....phew......

That is the promise of a new technique called EGIR or epidermal genetic information retrieval. A new company called DermTech has just developed the technique. So what is the technique and how does it work?

The tape collects RNA from the skin sample. The sample then was amplified as cDNA and a microarray checked for the 117 gene analysis. This technique was studied and a 5 gene profile was adopted and accurately differentiated melanoma from benign skin changes. This technique is being evaluated at University of California San Francisco.

The Sherpa Says: In general only 3-10% of suspicious lesions are actually melanomas. The traditional method to detect includes a scalpel excision.....Tape......Scalpel... You decide. However, this is only a small study that determined proof of concept. There is a replication study underway and despite being great for the patient, the dermatologist can't exactly bill for RNA extraction. They do get paid very nicely for skin biopsies though. Not quite for prime time, but it does demonstrate how ubiquitous genetic soon will be in the office.

The Danger in Genetics

My great friend Adam Messenger just sent me an article which I can't believe I missed. Late June in the New York Magazine there was an article entitled "The Science of Gaydar"

Has anyone read this article? After I did, I was very frustrated....

From the article-

"If sexual orientation is biological, are the traits that make people seem gay innate, too? The new research on everything from voice pitch to hair whorl"

I do not remember a time when sexual orientation was classified as a disease.......However that is only because I am young. Ask a host of physicians and they will tell you that until 1973 the American Psychiatric Association viewed it as a mental illness along the lines with bipolar disorder.

"Back then, many psychiatrists treated homosexuality with shock therapy, detention, or a mind-twisting intervention called “aversion therapy”—a practice that was still in vogue in the late seventies, when a lumpy-faced psychiatrist put me through a regimen of staring at Playboy centerfolds."

The author talks about how classical morphology is being used to evaluate for sexual orientation. I feel this is almost as if they are discovering a new "syndrome". If you examine all first print literature of genetic syndromes you find much the same associations.

In fact there is a book that lists standard and accepted measurements for moprhology. This book used to be a mainstay for skilled clinical geneticists. There is another textbook called Smith's Recognizable Patterns of Human Malformation. The piece made me feel as if sexual orientation was soon to be listed in this book!!!! I am certain this will make the public feel similarly.

"A large-scale study within the next year is expected to determine more conclusively if a gene (or genes) is linked to sexual orientation. Alan R. Sanders, a psychiatrist from Northwestern University, is enrolling 1,000 pairs of gay brothers in one of the largest sexual-orientation studies ever undertaken. With the experiment, funded by an NIH grant of over $1 million, Sanders will attempt to map genes that influence sexual orientation."

This will create the first data in a long time on the subject. The Xq28 stuff is really suspect and I am certain there will be a much different take once this "study" completes.

But I agree with the author on his final assumption.

"It’s bizarre to think some value systems might lump gayness in with—say—sickle-cell anemia or Down syndrome. As Matt Foreman from the Task Force put it, “It’s not playing with the number of toes you have; it’s really manipulating your very essence. So many people see gay people only in terms of sexual behavior, as opposed to what sexual orientation is really about, which is how you fit into the world. I don’t want to get mushy, but it’s about your soul.”"

The Sherpa Says: What I have a hard time with is the simple fact that morphology analysis is being used. Even worse is the use of the term "gay gene" Yes genetics will impact everyone's life, but must we go at sexual preference. Aren't there bigger things to answer? Yes there should be some study of things considered deviant: child molestation, rape, etc. But I thought homosexuality was declassified in 1973......I guess I was wrong. If deCODE or any other DTC company markets a "gay test" please do not go out and take it!!!!!!!! Please!!!

Tuberculosis, XDR-TB and Personalized Medicine!!

After all the talking and pundits, after all the media hype and fear. XDR-TB still remains a serious issue. True there seems to be significant irony in this case and that may make it stick around a while. What is XDR-TB? Well according to the CDC

"Extensively drug-resistant (XDR) TB – or TB that is resistant to at least two main first-line drugs (Isoniazid and Rifampin) and additionally to three or more of the six classes of second-line drugs"

So why post about tuberculosis in a personalized medicine/genetics blog? The answer is simple. There must be something in the genetics of host or bacteria that create this resistance. In addition there must be a way to test for these and prevent inappropriate treatment.

This treatment is dangerous at times even causing hepatitis and liver damage. A certain subset of people cannot handle isoniazid at all. These people have a problem with Nat2 and the inactivation of this medication. These people have been well reported on in the literature and it is clear that they get significant toxic effects from the first line therapy.

Recently this year there have been many publications on the molecular identification of resistance genes.

Several genes, including

katG, inhA, kasA and ahpC, have been associated with resistance to isoniazid. Recently rpoB and katG again.

More than 90% of rifampicin-resistant strains have been shown to possess point mutations in an 81-bp rifampicin resistance determining region of the rpoB gene. This is important because
recently, non-commercial molecular methods for rifampicin and isoniazid susceptibility analysis
have been described.

The problem is that this method is not widespread. Even worse, there exists geographically variability in resistance not related to genotype. However this has not stopped the patenting of resistance assays. I am certain their is a buck or two to be made off of the identification and proper treatment of this life threatening disease.

The Sherpa Says: XDR-TB is bad news, but soon we will have personalized microbial resistance tests to avoid dangerous and ineffective treatment. In addition we will have pharmacogenetic tests to prevent INH toxicity. Thus giving the right bug the right drug for the right host.

The Genomic Revolution AKA the birth of Personalized Medicine

An intriguing second post at the "official blog" for direct to consumer testing company DNA Direct brings some excellent points up.

These are points that I often use when trying to tell physicians what will happen if they don't learn genetics.

It often scares the hell outta 'em, or they say "nah no way, medicine is too complicated for the public to practice." Then they go back to practicing medicine the same way we have for the last century, microscopes, gram stains, and paper charts.

The problem has been festering away and the geneticists, internists and specialists have been asleep at the switch. A Summit was held on the subject Bruce Korf, president-elect of the American College of Medical Genetics realizes this. In fact he has been preaching about it for the last 6 years. You can read about it here, here and here.

Some questions

• Who prescribes your blood pressure meds? Your Internists/Family Practitioner


• Who refers you to specialists? Your Internists/Family Practitioner


• Who encourages you to quit smoking? Your Internists/Family Practitioner


• Who argues with insurance to get paid? Your Internists/Family Practitioner


• Who doesn't have the time to see you let alone continue their medical education? Your Internists/Family Practitioner

I am collaborating with Dr Korf as well as leaders in Genetics and Internal Medicine at Yale, Mount Sinai and Harvard to develop a curriculum for residents. The problems

1. Getting the residents to attend conferences on topics the perceive are of no use to them. (why is this? The reason: their instructors can't speak genetics let alone teach it)


2. Finding physicians who speak genetics and can teach genetics. (There are 83 Geneticists who have certification in Internal Medicine)


3. Getting Residents to understand Genetics (Most don't know introns aren't junk)

The solutions? Are tough. I think we need to teach the teachers, we also need to teach the medical students. Physicians have not changed our level of genetics understanding in the last 30 years. That's why they all think Huntington's is the prototypical genetic disease. When I tell them that MI is the new prototypical genetic disease they laugh. How can we fix these attitudes?

Even psychiatrists agree that genetics is important but they realize the lack of knowledge they have.

Whether it is your OB/Gyn missing indications for referrals 9 out of 10 times or 1 in 3 Internists who misinterprets a genetic test for APC. My oncology friends still don't understand mitochondrial inheritance.

Could the lay person do better? Maybe...But could they write a prescription for the Cox-2 Inhibitor they now should be taking? Who will send them to the surgeon? Who will admit you to the hospital? Who will read and review all the articles needed for your care? Who will?

The solution lies in your hands. The solution is to encourage your doctor to learn genetics. Ask him about DNA and your health, ask her about your drugs and your genes. Force the issue, read as much as you can. When your doctor refuses, leave her care. Find a doctor who will learn. But please, please, please don't leave it up to yourself.

The Gene Sherpa says: The solution is up to you. It is up to your doctor. It is up to all of us, together learning and teaching each other. To get the best health care possible. Delivered by a licensed health professional, not by Domino's..........Wake up people or Wal-Mart is where you will get your genomic revolution!!!

DNA mutation....Not so fast my friend.

Today results were released from a Genome Wide Association Study. This revolutionary type of research does promise to bring us closer to true personalized medicine. That being said........
The study published in Science today by DeCode and several academic institutions (U Penn, Duke, Emory) shows that a loci on Chromosome 9 (long arm) 21 has been linked to an increased risk of heart attack. This study was almost simultaneously replicated by Dr McPherson in Canada at the Ottawa Heart Institute. The study links are not up yet. I will post the abstracts when they are. This is exciting news, however.

1. This is just in a block of genome, not a gene per se
2. The risk with this polymorphism is 1.6-2 fold
3. In Scheuner's analysis of family history, the risk with one afflicted sibling is approximately 2.8 fold
4. As my good friend Dr Lei at Eye on DNA suggests, this will not change the way we practice medicine....yet. First we need to start teaching doctors how to take a family history, then we can move to QTLs and genotyping.

I hate to be the lead balloon but,

The Gene Sherpa Says: While interesting and it should help discover further causes of heart attack this DNA "test" is not even close to ready for prime time!

Gene Doping in Athletes

This week in EMBO reports (European Molecular Biology Organization) the dreaded issue of gene doping rears its ugly head. Normally I only report on genetics pertinent to your health. However this raises special interest for me. I was a college athlete and am fascinated by the extremes to which we would go to shave off that 0.5 second. This article raises significant questions about using gene therapy to enhance performance. Where will we stop, what line will be drawn? Gene therapy to cure disease....Why isn't weakness a disease? What about poor vision? We allow athletes to have LASIK, why not gene therapy? The danger is gene overdose. Once introduced into the body we have very poor mechanisms to control expression. But for that extra 0.5 seconds is it worth it? What about for those extra 200 points on the SAT?

The natural extension for these test yourself companies is now treat yourself. Are you a 100lb weakling? What about being predisposed to obesity? Treat yourself. Would you?

Drug overcomes mutations

Today in the Times Online an article introduces a new type of medication. Called PTC124, this medication allows ribosomes to "pass-over" nonsense mutations, allowing for fully transcribed protein. The functional properties of PTC124 are similar to the aminoglycoside antibiotic gentamicin, but the two compounds are chemically distinct and PTC124 does not exhibit any antibiotic characteristics. In vitro experiments showed PTC124 to be superior to gentamicin at ribosomal read-through of nonsense mutations. Currently the drug has passed Phase II trials of Duchenne Muscular Dystrophy and of Cystic Fibrosis

If we look at disease burden in rare genetic diseases, nonsense mutations(mutations coding for a stop sequence in the middle transcription, resulting in a truncated protein/mRNA) make up a significant amount of afflicted patients. Here is a press release from the company. It does turn out that this company is privately held, but I am sure Genzyme or another company is looking for a new M&A target.

Here's what the Gene Sherpa says, PTC124 could hold tremendous promise however I will await phase III trial results. There are always unanticipated outcomes, possibly tumorigenesis(cancer creation). Trials are currently recruiting if you are interested.That being said, we may see the development of other molecules designed to overcome our genetic shortcomings.

Lastly I just want to be perfectly clear about what I had said in a previous email. It may alienate me from other blogs, or hired gun blogs for certain DTC testing companies. Just look for the Gene Sherpa link. If it's gone on your favorite blogs, then chances are we have a shill.
When Han Solo told Luke that travelling through Lightspeed isn't like dusting crops I am certain he was talking about genetic testing. In home testing has no place in this world, unless it is guided by a TRAINED professional. I hope too many people will not be harmed by this senseless promotion of testing without counseling. No offense to other doctorates, but I took an oath to help or at least do no harm. Primum Non Nocere Unfortunately, most of the professionals marketing these tests have not. The physicians employed by them perhaps have forgotten this oath.

More on colon cancer.

While preparing to give a lecture on colon cancer for my curriculum study I came across another piece of evidence that should give most patients pause. I hope my readers take this to heart and begin assembling their own family histories. This week in the Journal of General Internal Medicine there is an article surveying patients about their experiences and screening offered for colon cancer prevention. The first survey identified patients with a family history of colon cancer and the second survey evaluated the care they received by their internist. The care was given at a Harvard affiliate! Here's what they found:

1. Only 39% of patients under 50 were asked about family history
2. Only 45% of patients with a significant family history had been screened appropriately
3. Only 46% of patients knew that family history of colon cancer can indicate a need for earlier cancer screening!

These averages might be good in baseball, but we are talking about human life here!

I am sure that with the database options in these new electronic medical records we will see more of our shortcomings. Especially when it comes to genetic care. That is if tracking family history is an option for an EMR. Most programs have woefully inadequate genetic options.

Here's what I will tell these young doctors: You better ask for family history, because the patient will not tell you they are at risk!

Here's what I will tell you: Please take your family's history and give it to the doctor, because they likely won't ask! More importantly, educate yourself about screening at the United States Preventative Services Task Force(USPSTF)

San Diego

I will be away for a few days. Just like Hsien Hsien I will be in California. Southern Cali for a conference. I will be presenting my findings on medical residents and their lack of genomic knowledge. Our group is a collaborative effort of Yale, Harvard, and Mount Sinai Schools of Medicine. What we found so far is scary, but not surprising. Especially after the story I told you yesterday. Residents with the most confidence in doing testing and family histories are the least knowledgeable about the subject with their average knowledge scores around 40-50%!!!!!
So beware residents asking family histories as well......Until I finish teaching them :)
See you on Wednesday!!!!

Skip the ritalin, get a genotype!!

This week in the American Journal of Psychiatry there is a study which links a specific haplotype(a few changes in the same copy of a gene) to ADHD onset. It is a confirmatory study(which is needed to draw any conclusions). The gene in question is the dopamine transporter DAT1. There has always been a familial risk of ADHD with identical twins being 70-90% likely to have the disease if their twin is afflicted. So naturally we have thought that this disease is primarily genetic. However, until lately the data did not indicate a significant role in DAT1 changes. But this literature is not very strong. Now there is a significant study, but this too needs some further investigation. Do I go out and get my kid tested for DAT1 polymorphisms? No. Does it give us hope for early identification of ADHD and other therapies besides a stimulant that stunts growth? You bet it does. Are there other ways to get ADHD without this gene change? You bet there are. That being said......
If there is a test and it is useful I will be the first to let you know.
Would you take the test?

Kidney Disease and your Child

This week in the official Journal of the American Academy of Pediatrics a study reveals that at least 2/3rds of nephrotic syndrome in the first year of life is caused by mutations in 4 genes. Those genes are NPHS1, NPHS2, WT1, LAMB2.
What does this mean for The Gene Sherpa? Well, incidentally it was found that these types of nephrotic syndrome are not responsive to steroids (No not the Barry Bonds type!). These medications are really strong types of anti-inflammatory. This is an example of personalized medicine! What would the non-savvy pediatrician do? Treat all nephrotic syndrome with steroids. Why? Because that is what she/he is taught. Unless you followed this literature you would be practicing trial and error medicine!

The Human Variome Project

Genes are like shoes, we each have a pair. Or in some instances (Homage to Imelda Marcos) several pair. As is the case with copy number variation(CNV). Let me explain, sometimes we have more than one pair of the same gene. It is a tough concept to get, primarily thanks to our "friend" The Monk. This is even more important than the idea of single nucleotide polymorphisms (SNPs). Simply put, with SNPs we differed approximately .1% millions of base pairs. Still there had to be more to the variation in humankind, and that's where CNVs come into play. This may lead to dosage effects of a certain protein or two. But how many copies does the average person have of each gene? Perhaps this will be discovered in the variome. The Wha?

The lead article in Nature Genetics this month describes the Human Variome Project. Much like the Human Genome Project, it will be a collaborative work. Much like the HGP, it will be another jumping off point for disease discovery and prevention. The project describes itself as " A global initiative that will catalogue all human gene variations – and will make that information freely available to researchers, clinicians and patients everywhere. "

I am excited about what this means. I have often been plagued by the dreaded Variant of Uncertain Significance. What that means in lay terms is "You're not quite normal, but you're not quite ill........Yet." It is one of the toughest things to counsel patients about and I hope the HVP will remedy that.

Google your genes part deux?

Not since Google partnered with Craig Venter in 2005 to start using the power of the genome have we heard a peep about the secrets that lie ahead for the two, well and possibly Ryan Phelan. CEO of that company which makes money off of testing people rather than a medical(yes genetics is medicine people) model. Stark II laws made it illegal for doctors to make profits from testing people, so why whould pseudo-medicine outfits be able?
Anyways, where was I? Oh Google.....
In this weeks HealthcareITNews there is an article on Google pushing for better health information on the web. Perhaps to harness the power of the two? Google your genes and then learn about the diseases you are predisposed to....All 50 of them :) This whole thing will not fly without doctors? Doctors are trained to build this list of 50 diseases and then whittle it down to 2 or 3. That being said, genetics is a different story. According the recent ACMG statistics the mean age of most geneticists is 52. There are also less than 1000 MD geneticists in the country! 20% plan to retire in the next 5 years. To fill their shoes? Less than half of the 150 training spots are filed. Google is starting to look like they have a chance. Even worse, in medical school the Association of American Medical Colleges ranks genetics as the 3rd most important topic yet none have a prerequisite of genetics in undergrad for entry. Your internist or pediatrician or Ob knows less about genetics than Google. Who will deliver the future and personalized medicine???? Not them. Maybe Google. Maybe cutting edge genetics practices that have specialized training?
What do you think?

Menopause, Hormones, and You

In the Wall Street Journal today there is a review article regarding recent literature published on menopausal hormone replacement. This article summarizes the debate regarding hormone therapy but does not get to the meat of an article published in the Journal of the American Medical Association(JAMA). The article has some controversy swriling around it. Mainly, that the p-value (likelihood of chance association) was adjusted after the analysis in response to a JAMA request. This is not usually standard practice for publishers as the p-value is usually accepted at 0.05. In this case it is 0.01. Either way the findings are what is interesting.

Traditionally the thought was that menopause and estrogen deficiency was a disease state. As such the "old time" doctors thought that hormone replacement helped prevent stroke and heart attack risk. This was flipped on its head in 2002 when the WHI released some findings which stated that you are actually at increased risk of heart attack or stroke while on the therapy!
This new study points out that there is a window of new onset menopause where therapy does lower risk, however in the elderly >70 years old there is an increased risk. I think that this study has some merit. However, the results can only be interpreted through a genomic eye. Recently data were released regarding ESR1(estrogen receptor alpha) and increased risk of heart attack in men. Currently there are no definitive data on whether estrogen PLUS some gene polymorphism put you at increased or decreased risk. When that data comes, rest assured that labs will be lining up the postmenopausal women. And when that data comes, you will hear it here First!

Genes for Heart Attack Risk/Prostate Cancer Risk

This week in the American Journal of Human Genetics 2 articles about genetic risk for heart attack are published. The findings raise hope of future therapeutic targets and identification of risks. The first study implicates the KALRN gene and an intronic(noncoding) SNP. This polymorphism(change in a gene) was found in almost all Caucasians with early heart attack. What does this mean? Very little so far. The results need to be replicated... But more importantly this gene operates in a totally different system than cholesterol in creating atherosclerotic plaques! The second study is more limited in scope and is less important for pan-ethnicity and only applies to French Canadians.

The news is just as exciting for African Americans as new studies implicated and corroborate other findings that a gene polymorphism could be responsible for up to 2/3rds of prostate cancer in this ethnic group. This set of data may lead to early detection or even prevention. This is the goal of all Personalized Medicine specialists....including myself!