Key genetic mutations could be new hope for adrenocortical tumor patients

April 4, 2014

Chinese researchers from Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, BGI, and other institutions have discovered that the activating hotspot L205R mutation in PRKACA gene was closely associated with adrenocortical tumors (ACTs), and the relationship of recurrently mutated DOT1L and CLASP2 with ACTs' other subtypes. The latest study published online in Science opens a new insight into diagnosis and treatment of Adrenal Cushing's syndrome.

Adrenal Cushing's syndrome results from autonomous production of cortisol (ACTH-independent) from adrenocortical tumors (ACTs), which may lead to a series of such as obesity, glucose intolerance and hypertension. However, the genetic architecture of Adrenal Cushing's syndrome remains largely uncharacterized, hampering the development of diagnostic and therapeutic approaches for Cushing's syndrome.

In this study, researchers performed whole-exome sequencing of 49 blood- pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), and adrenocortical oncocytoma (ADO). They found there was a hotspot L205R mutation in PRKACA gene, and two novel mutated genes that have never been reported: One is DOT1L, which may contribute the tumorigenesis of AIMAH; the other is HDAC9, which would be responsible for ADOs.

In the large-scale validation stage, researchers found that L205R mutation was only found in the ACTs, and located in the highly conserved functional domain-P+1 loop of PKA catalytic subunit-plays an important role in the combination of kinase and substrate. The further molecular and cell function validation proved that L205R mutation caused the increase of protein activity and enhanced the catalytic capability of the phosphorylation, and promoted the occurrence of tumor and the production of steroid by substrate phosphorylation.

Yanan Cao, Endocrinologist from Rui-Jin Hospital, said,"ACTs and Cushing's syndrome belong to one important kind of diseases in endocrine metabolic disorders. Our study revealed several key mutated genes closely associated with adrenocortical tumors. Furthermore, we systematically analyzed the function of L205R mutation by structure and molecular biology technologies, laying a solid foundation for developing new treatment strategies for Adrenal Cushing's syndrome."

Minghui He, Project Manager of BGI, said, "Using high-throughput sequencing and bioinformatics technologies, we characterized mutation landscape of adrenocortical tumor, and found L205R mutation in PRKACA gene was closely associated with adrenocortical tumors. These findings provide new insights into the clinical diagnosis and treatment of adrenocortical tumors."

Explore further: Signifor approved for Cushing's disease

Related Stories

Signifor approved for Cushing's disease

December 17, 2012

(HealthDay)—Signifor (pasireotide diaspartate) has been approved by the U.S. Food and Drug Administration to treat Cushing's disease in cases that cannot be treated by surgery.

UCLA-led team may have found key to cause of Cushing disease

May 31, 2013

Cushing disease is a life-threatening disorder most commonly triggered by tumors, often benign, in the pituitary glands, resulting in excess production of adrenocorticotrophic hormone (ACTH). The condition is marked by progressive ...

Are you carrying adrenal Cushing's syndrome without knowing it?

November 27, 2013

Genetic research that will be published tomorrow in the New England Journal of Medicine suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians' understanding and treatment of a form of Cushing's ...

Cushing's syndrome: A genetic basis for cortisol excess

February 27, 2014

An international team of researchers led by an endocrinologist at Ludwig-Maximilians-Universitaet (LMU) in Munich has identified genetic mutations that result in uncontrolled synthesis and secretion of the stress hormone ...

Recommended for you

Compound doubles up on cancer detection

October 8, 2015

Tagging a pair of markers found almost exclusively on a common brain cancer yields a cancer signal that is both more obvious and more specific to cancer, according to a study published last week in the Proceedings of the ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.