Pituitary Tumors in Cushing’s Have More Genetic Abnormalities: Study

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Pituitary tumors producing excessive amounts of adrenocorticotropic hormone (ACTH) — the most common cause of Cushing’s disease — carry more genetic abnormalities than those not generating excess ACTH levels, also called non-functioning tumors, a small study shows.

The data also identified two genes that may be involved in the transformation of non-functioning pituitary tumors into functioning, or ACTH-producing, lesions and/or more aggressive tumors.

Future studies with more samples from the several types of pituitary tumors are needed to confirm these findings, the researchers noted.

“We are currently increasing the number of samples to corroborate our findings and to be able to perform a more comprehensive … analysis of our data,” the team wrote.

The study, “The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas,” was published in the International Journal of Molecular Sciences.

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Cushing’s disease is commonly caused by benign pituitary gland tumors, called corticotroph pituitary adenomas, that overly produce ACTH. That hormone stimulates cortisol production by the adrenal glands, which sit atop the kidneys. Abnormally high cortisol levels are ultimately responsible for most Cushing’s symptoms.

In rare cases, pituitary adenomas become aggressive, grow faster, invade neighboring brain tissues, and respond poorly to treatment. Based on specific features, these aggressive tumors can be divided into several types.

Those that do not produce higher-than-normal ACTH levels and do not cause Cushing’s symptoms are typically called silent corticotroph adenomas, or SCAs, while those displaying a specific cellular feature called Crooke-hyaline are named Crooke cell adenomas — CCAs.

Aggressive pituitary tumors that spread, or metastasize, to other parts of the brain or spinal cord, or the rest of the body, are called pituitary carcinomas. Both CCAs and pituitary carcinomas may or may not overly produce ACTH.

Of note, pituitary tumors producing excessive ACTH levels and leading to Cushing’s are classified as functioning adenomas. Those not overproducing the hormone are called non-functioning tumors.

ACTH-secreting pituitary adenomas causing Cushing’s “are among the best genetically characterized pituitary tumors, with USP8 [mutations] occurring in up to 25–35% of sporadic cases,” the researchers wrote.

The USP8 gene provides instructions to produce an enzyme of the same name that regulates the stability and turnover of proteins involved in key cellular processes, such as cell growth and DNA repair.

Still, there is limited information on the genetic profile of the different types of pituitary tumors.

To learn more, a team of researchers in Mexico now used whole-exome sequencing (WES) to uncover genetic abnormalities in a host of tumor types. These included three SCAs, one non-functioning CCA, four functioning pituitary adenomas, one functioning pituitary carcinoma, and one functioning adenoma in a patient who developed Nelson syndrome.

WES looks at all of a person’s exons, the sections in a gene’s DNA sequence that provide instructions for making proteins. Nelson syndrome is a rare disorder in which an ACTH-producing pituitary adenoma grows faster — causing excessive ACTH-associated complications — after the adrenal glands are removed as a therapeutic approach for Cushing’s.

Genetic abnormalities evaluated through WES included the number of single-nucleotide variants (SNVs) and copy-number variations (CNVs). SNVs are changes in a single nucleotide — the DNA’s building blocks — while CNVs comprise the loss or repetition of large DNA sections.

All but one patient from whom the tumors were removed were female and their mean age was 38.8 (range, 17–61 years). Each of the tumors was larger than most corticotroph pituitary adenomas, which are typically smaller than one centimeter in diameter.

Results showed that about 18,000 genetic alterations were identified in these tumors. Moreover, several genes were affected by different types of mutations.

For many of these genetic changes, it is unknown whether they cause any harm, and further studies are needed to clarify this, the team noted.

Also, gains in genetic material were found in 44 large DNA regions, while DNA loss was detected in 72 regions.

The ACTH-producing pituitary carcinoma showed the highest mutational burden, in terms of both SNVs and CNVs.

When looking at genes previously associated with cancer, researchers found that each of these six genes — HSD3B1, TP53, CDKN1A, EGFR, AURKA, and USP8 — were mutated in at least two tumors.

All tumors carried single-nucleotide mutations in the HSD3B1 gene and all but one had SNVs in the TP53 gene. The four ACTH-producing pituitary adenomas were the only ones not carrying mutations in the CDKN1A gene, and SNVs in the EGFR gene were detected in six of the 10 tumors.

USP8 mutations were detected only in the functioning pituitary carcinoma and in the functioning adenoma that led to Nelson syndrome. None of the analyzed tumors showed SNVs in the USP48, BRAF, BRG1, or CABLES1 genes, which were previously reported in pituitary tumors.

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Further analyses showed significant associations between USP8 mutations and larger tumors, and between CDKN1A mutations and silent tumors.

The only CNV abnormality shared by all types of tumors was the gain of genetic material in a particular DNA region of chromosome 10 called 10q11.22.

Notably, amplification of a particular DNA region called 17q12 was found in ACTH-producing adenomas causing Cushing’s, all SCAs, and the CCA, “highlighting their benign nature” relative to the carcinoma, the team wrote.

The team then conducted additional analysis for a hypothetical sequential step transformation from an SCA to an ACTH-producing adenoma, and finally to an ACTH-producing carcinoma.

They found that a particular mutation in the ATF7IP gene (p.K529R) might be involved in the transition from an SCA to a functional pituitary adenoma. Additionally, a specific mutation in the MSH3 gene (p.I79V) might be required for a Cushing’s-causing ACTH-adenoma to evolve into a more aggressive tumor, the team noted.

These mutations have previously been associated with other types of tumors, and further studies are needed to clarify their link with pituitary tumors.

These findings highlight that “functioning ACTH-secreting lesions harbor more SNV and CNV than non-functioning ACTH adenomas,” and that “the ACTH-secreting [carcinoma] shows more genomic abnormalities than the other lesions, underscoring its more aggressive biological behavior,” the researchers wrote.

Given the small number of tumor samples included in this study, the team plans to collect more samples to confirm these results. The scientists noted that future research is needed to understand the roles of these genetic alterations in pituitary tumors.