Surprising Discovery Connects Rare Vascular Disease to Cancer Gene

scan of mouse blood vessel

Venous malformation (VM) in the skin of a mouse. The arrows point to areas where blood is pooling in the veins. The small red circles in the blood pools are red blood cells.

The history of medicine is full of unanticipated findings. Penicillin, x-rays, and even aspirin came about by chance.

Memorial Sloan Kettering scientists recently made one such discovery: A common, well-studied cancer gene also plays a key role in a seemingly unrelated disorder of blood vessels called venous malformation (VM).

VM is a rare condition that affects one in 10,000 people. The deformed blood vessels that characterize the disease cause pain and disfigurement and can lead to problems with the nervous, muscular, and digestive systems.

MSK’s findings led to the first-ever genetically engineered mouse model for VM, as well as promising avenues for treating this potentially very serious condition with targeted therapy.

“Such a serendipitous finding almost never happens, because research is so driven by the hypothesis,” says MSK cancer biologist Maurizio Scaltriti. “This is one of the few cases in 2016 when you can still see one of those completely accidental, penicillin-like findings.”

An Unexpected Finding in Lab Mice

Dr. Scaltriti and his colleagues in MSK Physician-in-Chief José Baselga’s laboratory were studying the formation of endometrial cancer in mice. The rodents were engineered to carry mutations in a gene called PIK3CA, which have been found in many tumor types. Unexpectedly, many of the mice developed symptoms that included paralysis and bulging veins under their skin.

“We knew right away that our findings were not a coincidence,” says graduate student Pau Castel, who was leading the research.

We knew right away that our findings were not a coincidence.
Pau Castel Graduate student

Further investigation revealed that malformed blood vessels around the animals’ spines were causing the paralysis. Such blood vessels, as well as the bulging veins, are hallmarks of VM.

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Zeroing In on a Rare Disease

José (left) and Eulalia Baselga

Sibling scientists José and Eulalia Baselga were surprised to find the connections between their research.

Once the researchers determined the mice were experiencing VM, they looked for a connection between PIK3CA mutations and the disease. Further studies, including genetic analysis of 32 MSK patients who had VM, confirmed the relationship. The team determined that about a quarter of all cases of VM are caused by PIK3CA mutations.

For Dr. Baselga, who was senior author of the study, there was another surprising finding. He acknowledges that the team didn’t know much about VM, but they were able to take advantage of a hard-to-believe coincidence. “It turns out that I knew one of the world’s leading experts in the condition — my sister Eulalia Baselga, an academic pediatric dermatologist in Barcelona,” he says. “So it was easy. I simply called her up. She told me, ‘I’ve been waiting for something like this for a long time. It opens up a true understanding of the disease.’”

Since the laboratory was already studying targeted therapies that block PIK3CA mutations in cancer, they prepared topical creams containing the drugs and applied them to the mice, which resulted in a measurable decrease in VM. The researchers confirmed that the drug in the cream was targeting VM in the same way it attacks cancer cells, by reducing the growth of defective cells and killing those that are already there.

Further studies in the lab are needed before these treatments can be evaluated in people. But because current therapies for VM don’t work very well, the investigators hope they can be available to patients quickly.

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This research, which was published in Science Translational Medicine, was funded by the Geoffrey Beene Cancer Research Center at MSK.


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My three-year-old granddaughter has Venous Malformations. Would this new treatment possibly help the 75% who do not have the cancer gene as well?

Karen, the idea behind this treatment is that it would specifically target the faulty proteins caused by the gene mutation. Some other gene mutations that cause the disease may ultimately result in the same faulty protein, but not all of them do. It’s also important to note that this is very early research, still being conducted only in laboratory mice, and it’s too soon to say whether this treatment will prove to be effective in patients and — if so — what percentage it would help. Thank you for your comment.

Does this mean that those with vascular malformations would be more susceptible to getting cancer?

Jessica, according to the researchers there is currently no clinical evidence to suggest an association between venous or lymphatic malformations and cancer. Thank you for your question.

My daughter has a venous lymphatic malformation, but it is mainly lymphatic. Could this new treatment be helpful for her?

Stacy, according to the researchers, some lymphatic malformations are also characterized by the presence of PIK3CA mutations. They think this treatment will also have an impact in this disease. However, additional studies are required before bringing this treatment to the clinical setting. Thank you for your comment.

I have KTS in my left leg. I am 50 now but I have had repeated skin cancers removed since I was 21. The doctors tell me I don't fit any of the norms for this. Lesions have always been in places that don't get the sun. I have not lived abroad etc. I have often wondered if linked to my KTS. So I am really interested in the research. Is there anymore I can find out? Thank you both for the jobs you do. So important.

Jan, we recommend you refer to the National Institute of Neurological Disorders and Stroke for the latest on research related to KTS. You can find their information page here:… On that page, there are links to information about KTS-related research studies (clinical trials) if you would like to learn more about this area of research. Thank you for your comment.

Jan, according to the researchers some cases of KTS, as well as similar overgrowth syndromes, may also be associated with PIK3CA mutations.

My son has a VM on his left heel, sense birth. He has had 9 sclerothreapy treatments. He also has a lymphatic VM behind his left ear, also tiny purple dots on random spots of his body. Is there anything that you can take naturally to fight off PIK3CA?

Hi Caitlyn, we’re sorry to hear about your son’s problems. As stated in the article, only about 25% of VM cases are caused by mutations in PIK3CA, so it is more likely than not that your son does not have this mutation. We recommend that you discuss your concerns with his doctor, as well as any supplements you may consider giving to him. Thank you for your comment.

Can you please explain further, how one know if they have that cancer gene. I never heard of this cancer, but there is cancer in my family. So I am curious.

I am 28yrs old and have been treated different ways for my Mixed Malformation in my right lower leg.

Hi Diana, as we explained in response to an earlier comment, there is currently no known connection between venous malformation and susceptibility to cancer, even though they appear to be connected by this gene mutation. In addition, the mutation that’s been linked to VM, in a gene called PIK3CA, is not necessarily something that is inherited or runs in families. It may occur by chance later in life. And it is only one of many genes that are linked to cancer. If you are concerned about your family history of cancer, you may want to speak to a genetic counselor. If you’re in the NYC area, you can call our Clinical Genetics Service at 646-888-4050 or go to… for more information. Thank you for your comment.

I am a 39 year old male with VMs. I had my first surgery at age 2, I am currently up to 56. This is amazing research. I host a group on Facebook with about 600 members that have or know someone that has VMs. I am so excited about some possible answers. Good Job!

Very, very interesting. I have a VM and was also diagnosed with stage IV cancer. I did not really have any of the known risk factors and actually had several people including physicians ask me if I had ever been told there may be a connection between the two.

Jennifer, we’re sorry to hear about your health problems. According to the researchers, venous, lymphatic, or arteriovenous malformations are not associated with increased cancer susceptibility. Thank you for your comment.

Have there been other gene mutations positively identified as causing vm and are they going to be looking into connections to any other kinds of cancers in these genes? My husband and his father both get skin cancer repeatedly. My son age 3 has a large multifocal vm on the left side of his face (same side my husband's worst cancer was). My son also has 2 additional small malformations, one near the optic canal and one on the right near his clavical. I gotta say, the possibility that in the future some people might be able to just apply a cream blows my mind. I pray you are able to develop something like this. How drastically different from what my son endures for treatment.

Nastasia, mutations in a gene called TEK are also known to cause VM, but TEK mutations have not been found in human cancers. It is important to note that venous, lymphatic, or arteriovenous malformations are not associated with increased cancer susceptibility. Best wishes to you and your family.

My daughter has arteriovenous malformation in her right leg. She is just 6 month old. CM-AVM SYNDROM . Our doctor thinks she might have a RASA 1 mutation in her blood. We still waiting for testing.
I'm wondering if the same thing will work to treat her? Thank you!!!

Julia, we’re very sorry to hear about your daughter. We sent your question to the researchers, who said that RASA1 mutations are known to be responsible for causing capillary malformation/arteriovenous malformations (CM-AVM). However, these RASA1 mutations activate a different pathway related to cell growth and survival, called the MAPK pathway. Currently, there is not enough evidence to know whether the therapies used in this study will be useful in RASA1-mutant CM-AVM. Thank you for your comment.

My son was born with a tongue venous malformation and a right ankle microcystc lymphatic malformation. He's had 6 surgeries(3YAG laser & 3 sclerotherapy one with endovascular laser. 13 years later, his tongue still has the same footprint and may even be thicker than before all these procedures. I wonder if he is among the 25% ? Regardless, this is fascinating research and discovery! The possibility of a targeted therapy makes me hopeful!

Hi, my 3 year old daughter has KHE/KMS, she was diagnosed at 4 weeks old. Reading this has raised a few concerns. Thank you for the research

Is the treatment referred to here Rapamycin (Sirolimus) or something new?

My son has an extensive venous malformation through his oral cavity, jaw, airway and oesophagus. Is it possible to test for the gene mutation. With the topical cream I hope that there is a way to attack the vm in his throat because this is obviously the biggest concern for us.

Renee, we’re sorry to hear about your son. This research is still at a very early, experimental stage and there is not a standard clinical test for the mutation in VM. Thank you for your comment, and best wishes to you and your family.

My son was diagnosed with CM-AVM Syndrome after doctors discovered he had a RASA 1 gene mutation.
Should we do further testing to see if he also carries the PIK3CA mutation as well?
Wondering if this mutation is found in those with AVM's or only with VM's?

Jenny, according to the researchers, although RASA1 mutations are known to be responsible for causing capillary malformation/arteriovenous malformations (CM-AVM), these mutations activate a different pathway related to cell growth and survival, called the MAPK pathway. Thank you for your comment.

My daughter was diagnosed with a hemangioma which covered the left side of her cheek and part of her eyelid when she was a few months old which ulcerated and a doctor informed us that part of the hemangioma had transformed into an AVM. She has undergone a number of surgeries as well as being treated with propranalol which has greatly improved but for any parent with a child diagnosed with a condition where Drs don't know what causes them is very distressing as it is usually guess work what will work and what won't. I cannot emphasise enough how valuable your discovery is and wish you the very best of luck in the future and hope it leads to being able to develop treatment options, you are the unsung heroes

Trace, we’re sorry to hear about your daughter. Thank you for your comment.

My Daughter is 38 years old,and has a vm,that wasn't found right away d/t the fact that no Drs. could find out what was causing her pain.We finally went to the Children's Hospital in Boston.She went every 3 maths. I can't remember how many times.The treatments caused her even more pain.She has stopped her treatments,many years ago.Her VM has spread from her left leg,up her back.She has an appointment with Dr.Hayes,in Colorado.Maybe this could help her?We live in upstate N.Y.,and we are looking still for anything that could make her life easier. Thank s

Sue, we’re sorry to hear your daughter is going through this. Unfortunately these possible new treatments are still very early in development and are not yet ready to be tested in patients, but we recommend that your daughter discuss this with her doctors in the coming years. Thank you for your comment, and best wishes to you.

My 27yr old son was born with a large hemangioma on his left hip and at 11yrs old diagnosed with Klippel-Trenaunay syndrome. He delt with the pain and other symptoms that come with this syndrome, so when he was 27yrs old and having pain and other symptoms he just figured it was his KTS, February 2016 he was diagnosed with stage 4 Metastatic Angiosarcoma, he suffered for 3 weeks the most excruciating pain, before he passed. doctors said it started in his KTS tumor, I could find only 2 other documented cases related to KTS. I truly hope this can help raise awareness.

Dear Cindy, we are very sorry to hear about the loss of your son. Thank you for sharing his story.

my 25y/o daughter has been diagnosed with microvascular AVM's of both lung bases. HHT genetic testing was all negative. she continues to decline and is now requiring continuous oxygen. last week she began having seizures. the doctors have her on high dose birth control. They really do not know what to do for her. I am wondering if she has cancer. we have strong hx of cancer in our family. in the past 2 years we have had a 25y/o testicular cancer 27 y/o thyroid cancer and 31y/o breast cancer. there is also ovarian cancer BRCA1, breast cancer and lung cancer. any words of wisdom would be greatly appreciated.

Peggy, we’re sorry to hear that your daughter is going through this. If you’d like to arrange for a consultation at MSK, you can call 800-525-2225 or go to for more information on making an appointment. If you’re concerned about your family history, you might want to speak to someone in our Clinical Genetics Service. They can be reached at 646-888-4050 and you can go to… for more information on genetic counseling. If you’re not in the New York City area, we recommend that you ask your doctor for a referral to a genetic counselor. Thank you for your comment.

Thank you so much for your research. My mother died of endometrial cancer the same year I was diagnosed with a vascular malformation in my spinal cord. I never dreamed they could be connected. I am currently on disability due to effects of the CVM. How can I stay up to date about further research and find out about the possibility of being involved in human trials. Thank you for your response.

Dear Kim, our condolences for your loss. We are also sorry to hear about your diagnosis. You should discuss possible trials with your doctor, and you can periodically browse through the studies listed on for updates. Thank you for reaching out to us.