Research News

In a new study published in npj Genomic Medicine, a research team led by Charis Eng, MD, PhD, has found that distinct metabolite profiles may be associated with either cancer or autism spectrum disorder (ASD) and/or developmental delay (DD) in individuals with PTEN mutations.

Germline (heritable) mutations of the tumor suppressor gene PTEN are associated with a spectrum of rare genetic disorders that increase the risk of certain cancers, cognitive and behavioral deficits, benign growths and tumors (i.e., hamartomas), and macrocephaly. These disorders are referred to collectively as PTEN hamartoma tumor syndrome (PHTS), but clinical manifestations vary widely among patients and often are difficult to anticipate at the individual level.

"Intriguingly, we have observed distinct subsets of PHTS patients with either cancer or ASD/DD based on metabolic profiles," said Dr. Eng. "Since being able to predict clinical outcomes will enable us to better treat and, ultimately, prevent disease in individual PHTS patients, we have been investigating potential modulators, such as metabolites, that may influence whether a patient develops cancer, ASD/DD or even both."

Conducting a comprehensive study of metabolites in PHTS patients

Dr. Eng's team previously pinpointed certain metabolites within the tricarboxylic acid cycle (a key metabolic pathway relevant to energy production) that may serve as predictive biomarkers to distinguish between PHTS patients who will develop ASD/DD and those who will develop cancer. However, the study was limited to a small targeted set of metabolites, so the findings represent only a partial snapshot of the metabolites that may influence ASD/DD and/or cancer outcomes in individuals with PHTS.

In this study, the researchers conducted a comprehensive study of all metabolites in a series of 30 PHTS patients (10 with cancer, 10 with ASD/DD, 10 with both) to determine if specific metabolites and/or metabolic networks are associated with the development of cancer or ASD/DD. The three groups were matched with respect to age and biological sex.

Their analysis identified multiple individual metabolites and metabolite combinations that significantly differed between the PHTS patients with cancer and those with ASD/DD. In addition, they identified a highly interconnected network of metabolites and signaling molecules that converge on the PTEN protein and associated signaling pathways, further indicating the metabolites' potential influence on the development of PHTS clinical outcomes.

"Overall, this study provides further robust evidence for the roles of relevant metabolites in PHTS-ASD/DD versus PHTS-cancer etiologies and their utility as biomarkers for more accurate risk prediction in individual PHTS patients," said Dr. Eng.

Dr. Eng is the inaugural chair of the Genomic Medicine Institute and inaugural director of the Center for Personalized Genetic Healthcare, which includes the PTEN Multidisciplinary Clinic (designated as a PHTS Clinical Center of Excellence by the PTEN Hamartoma Tumor Syndrome Foundation) for children and adults with a confirmed or possible diagnosis within the PHTS spectrum. She was the first to link PTEN to Cowden syndrome, which is a PHTS disorder, and to ASD.

Lamis Yehia, PhD, a research associate and Ambrose Monell Fellow in the Eng lab, and Ying Ni, PhD, assistant staff in the Center for Immunotherapy & Precision Immuno-Oncology, are co-first authors on the study, which was supported in part by the Ambrose Monell Foundation, the Breast Cancer Research Foundation, the Zacconi Program of PTEN Research Excellence, the American Cancer Society, the National Cancer Institute and the National Institute of Neurological Disorders and Stroke (both part of the National Institutes of Health).