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High Prevalence of Germline Variants in Rare Endocrine Tumors

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Researchers from the University of Tsukuba show that genetic variants are commonly associated in Japanese populations with two types of inherited tumor, pheochromocytoma and paraganglioma

Tsukuba, Japan—Certain kinds of tumors can be inherited within families. Identifying the underlying genetic cause is important in treatment, but most studies on these tumors have been carried out on Caucasian populations. Now, a research group at the University of Tsukuba have carried out the first comprehensive study of two types of inherited tumor in Japanese patients and shown that the overall frequency of genetic variation is comparable to that seen in European patients.

Some types of tumors have a single genetic variant as their cause, whereas others can result from a variety of underlying genetic changes, known as genetic heterogeneity. The two most common types of inherited tumors associated with genetic heterogeneity are both tumors of chromaffin cells, a particular cell type that can receive signals from the nervous system and release hormones. These two tumors arise in the adrenal gland (where they are known as a pheochromocytoma) or in the parts of the body that control blood pressure (where they are known as paraganglioma). Although they develop in different places, the two tumors have a common underlying pathology and genetic background and so are grouped together as pheochromocytoma/paraganglioma (PPGL).

Seven major genes have been identified as "susceptibility genes" for PPGL—that is, genes in which mutations can lead to an increased likelihood of tumor development. The team examined 370 cases of PPGL, 327 of which seemed to have no associated family history, known as "apparently sporadic" cases. After collecting clinical data and blood samples, the researchers sequenced the seven susceptibility genes to look for genetic variation.

"Almost a quarter of the apparently sporadic cases of PPGL turned out to have some underlying genetic variation in at least one of the seven genes," explains lead author Dr. Masato Yonamine.

One of the genes, known as SDHB, was mutated most often, and showed an association with metastatic tumors, which spread to other regions of the body. The team also identified nine genetic variants that had not previously been described.

"The results of our study will provide the fundamental data required for the PPGL genetic test to be covered by insurance in Japan," says senior author Professor Kazuhiro Takekoshi.

This work underscores the importance of carrying out genetic testing when cases of PPGL are diagnosed in Japan, not only to determine the appropriate treatment course for the patient but also to screen other family members who may be carrying genetic variants and are therefore at risk of developing PPGL.

This work was supported in part by Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS KAKENHI grant numbers 201128060B to Mitsuhide Naruse, 21591168 to Kazuhiro Takekoshi, 23591889 to Hisato Hara, 25460671 and 16K08961 to Yasushi Kawakami, and 17H04328 to Eijiro Nakamura). The funders had no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

Original Paper

The article, "Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma", was published in Cancers at DOI: 10.3390/cancers13164014


Professor TAKEKOSHI Kazuhiro
Faculty of Medicine, University of Tsukuba

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