Rapid Results: MSK Researchers Link Genetic Mutation to Rare Bladder Cancer

David Solit

David Solit addresses riders at a Cycle for Survival event in Washington, DC, on March 5.

Two initiatives unique to Memorial Sloan Kettering — MSK-IMPACT™, a groundbreaking genetic test, and Cycle for Survival, a nationwide series of indoor cycling events that raises money for rare cancer research — have helped produce an important discovery about a rare, aggressive form of bladder cancer in a short time. The finding will help guide treatment decisions and shed light on how the disease develops so that researchers can design better therapies.

The disease, plasmacytoid variant carcinoma, accounts for 2 percent of muscle-invasive bladder cancer cases in the United States each year — approximately 300 people. It spreads early, recurs quickly after surgery, and is resistant to chemotherapy.

MSK researchers have now identified a mutation in a gene called CDH1 that plays a central role in triggering the runaway invasion that is the hallmark of this cancer.

 “Prior to this study, we did not understand why this form of bladder cancer was so aggressive,” says David Solit, Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO). Dr. Solit led the research, which was recently published in Nature Genetics. “This discovery is a major step toward improving the treatment of patients with this rare cancer.”

Fast Research Results

This finding was largely made possible by two innovative MSK programs. The first, MSK-IMPACT, is a genetic test now used routinely to analyze tumors in MSK patients with advanced cancers. MSK-IMPACT helps clinicians understand what makes individual tumors grow and spread and is used by oncologists to match patients with appropriate standard therapies or investigational clinical trials. The diagnostic test, now entering its third year, recently reached a milestone when it sequenced its 10,000th patient tumor.

The second initiative is Cycle for Survival, a philanthropic program that raises money for rare-cancer research through indoor cycling events held in multiple cities each year in February and March. Since 2007, Cycle for Survival has raised more than $100 million to support research projects focused on identifying treatments for rare cancers, which make up almost 50 percent of all cancers.

This study highlights what is so special about Cycle for Survival. It supports the kind of research that is very rarely funded by the National Institutes of Health because it concerns a very rare tumor type.
David B. Solit MSK physician-scientist

Dr. Solit is an enthusiastic supporter of and participant in Cycle for Survival. He says this discovery represents a striking example of how quickly fund-raising for rare cancers can produce significant advances. The research took only a few years from its start to the publication of the findings.

“This study highlights what is so special about Cycle for Survival,” he explains. “It supports the kind of research that is very rarely funded by the National Institutes of Health because it concerns a very rare tumor type. Unfortunately, the patients who have this disease do very poorly, and new treatments are desperately needed.”

Back to top

The Telltale Mutation

For the study, the researchers performed genetic sequencing on plasmacytoid variant bladder tumors and found that most had a mutation in CDH1. Many of the tumors analyzed in the study had been sequenced by MSK-IMPACT as part of the patients’ clinical care. The test looks for abnormalities in more than 400 of the most important cancer-related genes.

VIDEO | 00:49
Dr. Jonathan E. Rosenberg discusses the promise of the new immunotherapy drug atezolizumab for bladder cancer.
Video Details

Dr. Solit emphasizes the importance of MSK-IMPACT’s contribution to the research.

“Tumor sequencing is rapidly changing the way cancers are diagnosed and patients are treated,” Dr. Solit says. “Now that we’ve identified this critical disease-causing mutation, we can correctly classify the disease earlier in the patient’s treatment course and potentially direct such patients to investigational approaches. If a patient has the CDH1 mutation, we know there will be a very high risk of the cancer returning after surgery, so that’s a strong argument for adding additional therapy around the time of surgery.”

Back to top

Cause for Optimism

One potential treatment that could benefit this patient group is a new immunotherapy drug called atezolizumab that is showing great promise against bladder cancer. A recent report in the journal Lancet describes encouraging results from a clinical trial led by MSK medical oncologist Jonathan Rosenberg.

The same type of drug has already proven effective against several other cancers, including melanoma and lung and kidney cancers. If approved, this would be the first new therapeutic advance for metastatic bladder cancer in more than 25 years.

“This new form of immunotherapy is something that we would want to try early in patients with plasmacytoid variant bladder cancers,” Dr. Solit says. “In addition, our genetic research has revealed other co-occurring mutations that possibly could be targeted with new or existing drugs. Going forward, we hope Cycle for Survival funding for similar projects investigating other rare cancers will allow us to replicate this approach.”

Back to top


Commenting is disabled for this blog post.

CDH1 gene is also an indicator for Hereditary Diffuse Gastric Cancer and Lobular Breast Cancer. Any indication if the new immunotherapy drug called atezolizumab helps those patients? If you have HDGC are you consequently more likely to also present w an aggressive bladder cancer?

Sally, thank you for reaching out. We consulted with MSK physician-scientist David Solit, who responds:

“There is definitely promising early data with immunotherapy in patients with gastric cancer. The data in lobular breast cancer is less clear but there are many immunotherapy trials for both diseases ongoing at MSKCC that should better clarify this question very soon.”

My dad was just diagnosed with plasmacytoid bladder cancer, they just did the cystectomy. Still in recovery. Please help. What should i am the doctor? Treatment?

My 98 year old Mom was just diagnosed with squamous cell bladder cancer. NYC is a long travel for her. Is there a center closer to a 12590 zip code
which specializes in this type of cancer where I could drive her?
Thank you

Dear JoAnn, we’re sorry to hear about your mom’s diagnosis. Because of her age, we recommend she consult with an oncologist who is experienced in treating geriatric patients. The best place to start is probably by looking at the National Cancer Institute’s list of designated cancer centers. You can find it at https://www.cancer.gov/research/nci-role/cancer-centers. Thank you for your comment, and best wishes to you and your family.

I have a growth in my bladder which has been removed three times ( just on the inner layer )over the past two years. Now it's back.
I go back to the Hospital ( as an outpatient ) in two weeks for the third cystoscopy for removal of this 1 cm size ( looks like cauliflower ) growth. Then await pathology results . Then back in hospital for another scrapping to insure no bad cells were missed.
I had 6 weeks of BCG three ( or so ) months ago. Did not help. Its back .
Questions 1. . Looking for help can MSK help ?
2. I plan to call MSK today Monday 12/4 to discuss. and see what the next step is ?
3. Can I have my full records sent to MSK ASAP.
4. Can I have some of the growth sent to ( or have a family member deliver direct to MSK pathology dept. From my hospital in the Albany NY area ?

I hope we can do this ASAP since my surgery is 12/19/17
Thank you

Does the link to a gene mutation mean that the plasmacytoid bladder cancer is more likely to run in families?

Dear Arthur, the mutation discussed in this story is somatic, not germline. That means that it is something that is acquired at some point in the formation and/or growth of the tumor, and not one that the person has carried in their DNA from birth. So no, it does not run in families. Thank you for your comment.