PTEN Research Provides New Insight on Inherited Cancers and Potential Predictors

Findings suggest targeted clinical approach

Charis Eng, MD, PhD, Chair and Founding Director of Cleveland Clinic’s Genomic Medicine Institute, has spent much of her career identifying genes associated with inherited cancers. Her intent is always gene-based diagnosis, prediction of cancer risk in the genetic counseling setting, and tailoring early detection and prevention strategies to the gene — in other words, precision medicine.

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Her group’s latest work suggests a new clinical approach for some women with endometrial cancer, a disease that affects more than half a million women in the United States. The National Institutes of Health (NIH) estimates that 52,630 women were diagnosed with endometrial cancer in 2014, and that it caused 8,590 deaths.

While most endometrial cancers arise sporadically, two known inherited syndromes account for a minority of cases. One, Lynch syndrome, is also associated with colon cancer and is well-described. Current guidelines recommend that all women diagnosed with endometrial cancer be screened for it.

Cowden syndrome link

The new study by Dr. Eng’s group suggests that certain women with endometrial cancer should also be screened for Cowden syndrome, an inherited disorder that occurs in an estimated 1 in 200,000 people and is characterized by multiple non-cancerous hamartomas and several specific cancers, including breast, thyroid, colon, kidney and skin. The connection with endometrial cancer has only recently been recognized and described by Dr. Eng and others.

Cowden syndrome and the more loosely defined Cowden-like syndrome are associated with germline alterations in four specific genes:

  • A mutation in the cell-division regulator/tumor suppressor phosphatase and tensin homolog (PTEN)
  • Methylation of the KLLN gene, which is also believed to act as a tumor suppressor
  • Variations in two genes that encode succinate dehydrogenase (SDHB/SDHD), an enzyme related to energy production.

In their international, multicenter prospective study recently published in Cancer, Dr. Eng’s group found that 7 percent of the 371 endometrial cancer patients enrolled in the trial had germline PTEN mutations, 10.5 percent had KLLN methylation, and 9.8 percent had SDH variations.

Clinically, the women with PTEN mutations were more likely than those without the mutation to be younger than 50 years of age, to have macrocephaly, to have a heightened risk for Cowden syndrome based on a score developed at Cleveland Clinic, to have low levels of the PTEN protein, and to have co-existing kidney cancer.

Women with KLLN methylation were also younger and had higher Cowden syndrome scores than were women without that alteration. No specific predictors were found for the SDH variants.

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“Our research demonstrates that inherited endometrial cancer isn’t always Lynch syndrome, the most common inherited adult-onset colon cancer syndrome. Our paper shows that you have to think of Cowden syndrome too, because there’s a whole list of other cancers that people with Cowden syndrome are at risk for,” Dr. Eng says.

While the results need to be independently replicated, Dr. Eng says the findings suggest a new targeted clinical approach: Women younger than 50 diagnosed with endometrial cancer should have their head circumference measured. If the measurement is larger than normal — 2 standard deviations above the mean, or about 58 centimeters — the patient should be referred to a cancer geneticist for evaluation to determine if testing is warranted for the specific genetic alterations associated with Cowden syndrome.

Need for Screening

Women identified as having PTEN-related Cowden or Cowden-like syndrome should be intensively and regularly screened for the other associated cancers, and counseled regarding their own prognosis and that of other family members.  (Dr. Eng and colleagues have developed detailed protocols.)

This study also suggests that the same approach is warranted for women with germline KLLN methylation, the most recently-discovered Cowden-associated alteration. First described in 2008, KLLN methylation is particularly associated with breast and kidney cancer. Much more work is needed to elucidate the KILLIN protein’s normal function, Dr. Eng notes.

A History of PTEN Discoveries

The current study represents just the latest of a long list of PTEN research contributions from Dr. Eng, who first identified germline PTEN mutations in Cowden syndrome patients in 1997 while at Harvard’s Dana-Farber Cancer Institute.

Two years later, she showed that PTEN mutations also increase the risk of breast and thyroid cancer, and subsequently at Cleveland Clinic Dr. Eng definitively demonstrated associations and lifetime risks of these and the additional cancers.

In 2001, Dr. Eng coined the term PTEN hamartoma syndrome (PHTS) to designate patients who share the gene variant but exhibit various phenotypes in addition to Cowden syndrome, including the congenital disorders Bannayan-Riley Ruvalcaba syndrome, PTEN-related Proteus syndrome and Proteus-like syndrome.

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In 2011 after a rigorous prospective study lasting more than a decade, Dr. Eng and her team derived a risk calculator resulting in the PTEN Cleveland Clinic Score. The assessment tool estimates the probability of having a PTEN mutation, to help caregivers decide who and when to refer to cancer genetics professionals.

Just last year, Dr. Eng’s team also demonstrated that individuals with PTEN mutations are not only at risk for several types of cancers, but for subsequent primary cancers.

Dr. Eng and her group were also the first to demonstrate a link between PTEN and autism in children. They recently received an NIH grant to investigate the use of the cancer drug rapamycin as a potential suppressor of abnormal signaling pathways in children with autism and PTEN mutations.

Dr. Eng founded the multidisciplinary PTEN/Cowden syndrome clinic soon after she joined Cleveland Clinic in 2005. Since then, hundreds of patients and families have been referred from around the world. “We look after patients by the gene and the gene pathways rather than by organ system,” she says. “This is 22nd Century precision medicine.”

Dr. Eng is Chair and Founding Director of Cleveland Clinic’s Genomic Medicine Institute. She is also a Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine. She can be reached at or 216.444.3440.

Photo credit: Russell Lee Photography