Research News

The results were staggering but not completely unexpected. As Charis Eng, MD, PhD, Genomic Medicine Institute chair, reviewed the updates from her 20-year study of Cleveland Clinic’s PTEN Cohort, she calculated that previous short-term studies had greatly underestimated the lifetime cancer risk for individuals with PTEN Hamartoma Tumor Syndrome (PHTS). Though check-ins on her patients’ health revealed an association with cancer, the most recent study proved an alarming truth: those with PHTS have significantly elevated lifetime risks for multiple cancer types, including breast (91%), endometrial (48%), thyroid (33%), kidney (30%), colorectal (17%) and melanoma (5%).

Dr. Eng has spent her entire career researching PHTS, which stems from germline mutations in the PTENgene. People with PHTS may experience any combination of the seemingly disconnected symptoms, including multiple overgrowth disorders (one is the inspiration for the 1980 David Lynch movie “The Elephant Man”), several cancer types and autism spectrum disorder.

“Over half of my adult patients have developed some type of cancer, and 15% of my pediatric patients did, too.” said Dr. Eng. “I had anecdotally known this from experiencing and diagnosing it in real time, but it’s hard to fully understand the reality until you sit down and do the math.”

The findings, published in April in JAMA Network Open (just in time for PHTS awareness month in May), showed approximately 65% of the PTEN cohort – a group of more than 700 patients with PHTS who serve as research participants – developed three or more separate cancers over the years, and 30% developed at least four different cancers during the study.

The numbers, Dr. Eng says, are a warning for doctors to develop more intensive cancer screening protocols for individuals with germline mutations in their PTENgene. The discovery, and potential update to PTEN treatment guidelines, is an example of the power of these long-term, diverse studies and connecting with patients.

“The benefit of working directly with these individuals is knowing the story behind each test tube of DNA,” says Lamis Yehia, PhD, first author on the study who shadows Dr. Eng at the PTEN Clinic. “Patients often share their challenges, triumphs and milestones. It gives our research a profound meaning.”

“Patients often share their challenges, triumphs and milestones. It gives our research a profound meaning.” – Lamis Yehia, PhD

Conducting research together with PHTS patients

Dr. Eng works directly with PHTS patients at the PTEN Multidisciplinary Clinic and Center of Excellence, which attracts patients from all over the world for treatment. She says the PHTS patient community is close-knit, and before the data were finalized, patients had already told her cancer diagnoses seemed to be rising in their group. The pattern also showed up in online patient testimonials.

Dr. Eng, also chair of the Center for Personalized Genetic Healthcare, has worked with individuals affected by PHTS since 1997, when she first linked the PTEN gene to an overgrowth disorder called Cowden Syndrome.

Since then, Dr. Eng and her team have recruited over 7,000 individuals worldwide to their research study. Approximately 701 of the patients had PHTS and thus qualified to be in the “PTEN Cohort.” The overall goal of recruiting this cohort was simple: monitor the same group of people for over 20 years to understand the progression of the disease in the short- and long- term.

The number and diversity of the PTEN cohort has allowed Dr. Eng and her team to recognize patterns that would be overlooked in smaller groups and observe the full spectrum of ways PHTS can manifest.

“Twenty years is a long time to work with the same group of patients,” says Dr. Eng. “The relationship between our patients and our caregivers is extremely close. It is like a family.”

"[My patients are] proud that their contributions to research helped others like them receive the best possible healthcare.” – Charis Eng, MD, PhD

Raising awareness and informing patient care

Observations from the PTEN Clinic and cohort directly influenced national guidelines on patient care for PHTS, and for the individual conditions under the PTEN umbrella.

After a disproportionate number of her patients and their families that she followed had autism diagnoses, Dr. Eng's research established PTEN as one of the most common genetic causes of autism. The gene is now regularly included in genetic screens. After years of interacting with these families, Dr. Eng and her team were able to determine that individuals with PTEN-associated autism exhibited distinct behaviors from others with autism.

Now, caregivers know that patients with neurological disorders who test positive for a PTENmutation may require specific accommodations and care.

“My patients often tell me how excited they are to work so closely with us,” Dr. Eng says. “They tell us that they often know more about PHTS than their local physicians, and they’re proud that their contributions to research helped others like them receive the best possible healthcare.”

Cleveland Clinic already has increased cancer surveillance for these individuals from observations and previous studies – Dr. Eng’s 10-year update from the PTEN Cohort foreshadowed these results. The most recent data makes a case for other hospitals to do the same.

“Patients endure so much, and this is why we do what we do,” says Dr. Yehia, “Dr. Eng always tells me that ‘knowledge is power.’ It has been, and continues to be, such an honor to have the power to directly impact the quality and scope of care a patient receives.”