In the JournalsPerspective

ATRX mutation possible biomarker for rare neuroendocrine tumors

A somatic mutation in the ATP-dependent helicase, or ATRX, gene — recently demonstrating potential as a molecular marker for aggressive brain tumors — could also serve as a biomarker for rare neuroendocrine tumors, according to research published in Nature Communications.

“We have identified, for the first time, somatic ATRX mutations in pheochromocytomas and paragangliomas,” Katherine Nathanson, MD, of the division of translational medicine and human genetics, department of medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Endocrine Today.

Kate Nathanson

Katherine Nathanson

Although typically benign, pheochromocytomas and paragangliomas (PCC/PGL) turn very aggressive on becoming malignant, according to a press release.

“In our data set, they appear to be associated with more aggressive disease, but other studies should be done for external validation,” Nathanson said.

Inherited mutated genes, including VHL and RET, have been linked to the tumors forming in the center of the adrenal gland or among the nerve ganglia, but little is known about the somatic genetic changes leading to tumorigenesis, according to the release.

“In the future, somatic ATRX mutations may be identified through tumor testing, and be a biomarker of aggressive disease in this tumor type,” Nathanson said.

Nathanson, with Lauren Fishbein, MD, PhD, of the division of endocrinology, diabetes and metabolism at the Perelman School of Medicine, and colleagues used whole-exome sequencing on a set of 21 germline DNA samples of sporadic or inherited PCC/PGL; these are the solid tumor type most frequently associated with an inherited susceptibility syndrome.

The researchers looked for markers of malignant potential by comparing benign and clinically aggressive tumors. Somatic ATRX mutations were seen in two of seven tumors associated with germline succinate dehydrogenase B (SDHB). The scientists also sequenced the ATRX coding region in a distinct set of 103 tumors samples to quantify the frequency of somatic ATRX mutations in PCC/PGL; 13% of tumors showed ATRX mutations.

The sample set of PCC/PGL with ATRX variants is not large enough to identify statistically significant associations, according to the researchers. But clinically aggressive features, inherited SDHx mutations and alternative lengthening of telomeres suggest an interaction between somatic and inherited genomes in solid cancers and warrant further research, they wrote.

“For pheochromocytomas and paragangliomas, currently there is no reliable marker of aggressive or potential malignant disease other than an inherited SDHB mutation,” Nathanson said. “However, further studies should be done to validate these findings before any clinical implementation.”

Studies involving larger sample sets of PCC/PGL, such as The Cancer Genome Atlas rare tumor project, will be helpful, she added. But other research specific to mutated ATRX also is necessary.

“Studies of aggressive and metastatic tumors are needed in particular to confirm whether ATRX mutations are a biomarker,” Nathanson said. “Additionally, functional studies of ATRX mutations in this disease type will be important to understand its biological role.”

Clinical practice guidelines released by the Endocrine Society in 2014 offer evidence-based guidance for the management of patients with PCC/PGL

“The Endocrine Society guidelines on PCC/PGL go a long way to recommend consideration of clinical genetic testing for all patients with these tumors,” Fishbein said in the press release. “It is especially important to identify SDHx mutation carriers who have higher incidence of multifocal disease and SDHB mutation carriers at higher risk of malignant disease.” – by Allegra Tiver

Disclosure: The researchers report no relevant financial disclosures.

A somatic mutation in the ATP-dependent helicase, or ATRX, gene — recently demonstrating potential as a molecular marker for aggressive brain tumors — could also serve as a biomarker for rare neuroendocrine tumors, according to research published in Nature Communications.

“We have identified, for the first time, somatic ATRX mutations in pheochromocytomas and paragangliomas,” Katherine Nathanson, MD, of the division of translational medicine and human genetics, department of medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Endocrine Today.

Kate Nathanson

Katherine Nathanson

Although typically benign, pheochromocytomas and paragangliomas (PCC/PGL) turn very aggressive on becoming malignant, according to a press release.

“In our data set, they appear to be associated with more aggressive disease, but other studies should be done for external validation,” Nathanson said.

Inherited mutated genes, including VHL and RET, have been linked to the tumors forming in the center of the adrenal gland or among the nerve ganglia, but little is known about the somatic genetic changes leading to tumorigenesis, according to the release.

“In the future, somatic ATRX mutations may be identified through tumor testing, and be a biomarker of aggressive disease in this tumor type,” Nathanson said.

Nathanson, with Lauren Fishbein, MD, PhD, of the division of endocrinology, diabetes and metabolism at the Perelman School of Medicine, and colleagues used whole-exome sequencing on a set of 21 germline DNA samples of sporadic or inherited PCC/PGL; these are the solid tumor type most frequently associated with an inherited susceptibility syndrome.

The researchers looked for markers of malignant potential by comparing benign and clinically aggressive tumors. Somatic ATRX mutations were seen in two of seven tumors associated with germline succinate dehydrogenase B (SDHB). The scientists also sequenced the ATRX coding region in a distinct set of 103 tumors samples to quantify the frequency of somatic ATRX mutations in PCC/PGL; 13% of tumors showed ATRX mutations.

The sample set of PCC/PGL with ATRX variants is not large enough to identify statistically significant associations, according to the researchers. But clinically aggressive features, inherited SDHx mutations and alternative lengthening of telomeres suggest an interaction between somatic and inherited genomes in solid cancers and warrant further research, they wrote.

“For pheochromocytomas and paragangliomas, currently there is no reliable marker of aggressive or potential malignant disease other than an inherited SDHB mutation,” Nathanson said. “However, further studies should be done to validate these findings before any clinical implementation.”

Studies involving larger sample sets of PCC/PGL, such as The Cancer Genome Atlas rare tumor project, will be helpful, she added. But other research specific to mutated ATRX also is necessary.

“Studies of aggressive and metastatic tumors are needed in particular to confirm whether ATRX mutations are a biomarker,” Nathanson said. “Additionally, functional studies of ATRX mutations in this disease type will be important to understand its biological role.”

Clinical practice guidelines released by the Endocrine Society in 2014 offer evidence-based guidance for the management of patients with PCC/PGL

“The Endocrine Society guidelines on PCC/PGL go a long way to recommend consideration of clinical genetic testing for all patients with these tumors,” Fishbein said in the press release. “It is especially important to identify SDHx mutation carriers who have higher incidence of multifocal disease and SDHB mutation carriers at higher risk of malignant disease.” – by Allegra Tiver

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Richard J. Auchus

    Richard J. Auchus

    If a patient has a genetic mutation in a susceptibility gene, something else has to happen to make those cells become a tumor. It is obvious there has to be a second hit.

    This paper is a very good, important first step into thinking about these second hits — particularly for tumors with genetic susceptibility, and for pheochromocytomas and paragangliomas — and understanding what those second hits might be.

    In this case, 10% to 15% of the pheochromocytomas and paragangliomas have an ATRX mutation. The mechanism of how ATRX mutations drive tumor formation is not totally clear, because these tumors are associated with aggressive (metastatic) behavior, and loss of ATRX function causes changes in telomere length. Telomere length is associated with cell survival and resistance to senescence, but that alone does not explain metastasis. It does help to explain the tumorogenesis, but might not explain the aggressive behavior. Also, the ATRX mutations are found in only 10% to 15% of tumors — there must be other “drivers.”

    There is clearly a lot more we need to understand — not just in these tumors with the ATRX mutations, but in other tumors that must have something else lurking.

    • Richard J. Auchus, MD, PhD
    • Professor of Internal Medicine, Endocrine Oncology Program, University of Michigan Director, Metabolism, Endocrinology & Diabetes Fellowship Program

    Disclosures: Auchus reports no relevant financial disclosures.