Pituitary tumors that produce excessive amounts of adrenocorticotropic hormone (ACTH) – the most common cause Cushing’s disease Carry more genetic abnormalities than those without excessive ACTH levels, also called nonfunctioning tumors, a small study showed.
The data also identified two genes that may be involved in converting nonfunctioning pituitary adenomas into functional, ACTH-producing, and/or more aggressive tumours.
The researchers noted that future studies with more samples from several types of pituitary tumors are needed to confirm these findings.
“We are currently increasing the number of samples to confirm our findings and to enable a more comprehensive analysis of our data,” the team wrote.
Cushing’s disease is common it causes By benign pituitary adenomas, which are called cortical pituitary adenomas, which overproduce ACTH. This hormone stimulates the production of cortisol by the adrenal glands, which are located above the kidneys. Abnormally high cortisol levels are ultimately responsible for most Cushing’s disease symptoms.
In rare cases, pituitary tumors become aggressive, grow faster, invade nearby brain tissue, 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 levels of ACTH and do not cause Cushing’s symptoms are called silent cortical adenomas, or SCAs, while those that show a specific cellular feature called Crooke-hyaline are called Crooke-hyaline cell adenomas – CCAs.
Aggressive pituitary tumors that spread or metastasize to other parts of the brain, spinal cord, or the rest of the body are called pituitary cancer. Both CCAs and pituitary carcinomas may or may not produce excessively ACTH.
It should be noted that pituitary adenomas that produce excessive levels of ACTH and lead to Cushing’s disease are classified as functioning adenomas. Those that do not overproduce the hormone are called nonfunctioning tumors.
ACTH-secreting pituitary adenomas that cause Cushing’s disease “are among the best genetically characterized pituitary adenomas, with USP8 [mutations] They occur in up to 25-35% of sporadic cases.”
The USP8 The gene provides instructions for the production of 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.
However, there is limited information on the genetic specification of different types of pituitary adenomas.
To find out more, a team of researchers in Mexico has now used whole-exome sequencing (WES) to detect genetic abnormalities in a range 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’s syndrome.
WES looks at all of a person’s exons, which are the sections in a gene’s DNA sequence that provide instructions for making proteins. Nelson’s syndrome is a rare disorder in which an ACTH-producing pituitary adenoma grows faster–causing excessive ACTH-related complications–after removal of the adrenal glands as a Cushing’s therapeutic approach.
Genetic abnormalities assessed through WES included number of single nucleotide variants (SNVs) and copy number variations (CNVs). SNVs are single nucleotide changes – the building blocks of DNA – while CNVs involve the loss or duplication of large portions of DNA.
All patients with tumors removed were female, and their mean age was 38.8 (range, 17–61 years) except for one patient. Both tumors were larger than most cortical pituitary adenomas, which are usually less than 1 centimeter in diameter.
The results showed that about 18,000 genetic alterations were identified in these tumors. Moreover, several genes were affected by different types of mutations.
The team noted that for many of these genetic changes, it is not known whether they cause any harm, and more studies are needed to clarify this.
Also, gains in genetic material were found in 44 large DNA regions, while DNA loss was detected in 72 regions.
ACTH-producing pituitary carcinomas 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 – HSD3B1And TP53And CDKN1AAnd EGFRAnd orcaAnd USP8 – They mutated at least two tumors.
All tumors carried single-nucleotide mutations in HSD3B1 The gene and all but one had SNVs in TP53 gene. The only four ACTH-producing pituitary adenomas that did not carry mutations in CDKN1A Gene and SNVs in EGFR The gene was detected in six of the 10 tumors.
USP8 Mutations were only detected in functional pituitary carcinoma and in the functional adenoma that led to Nelson’s syndrome. None of the tumors analyzed showed SNVs in USP48And BRAFAnd BRG1or 1 . cables Genes previously reported in pituitary adenomas.
Further analyzes showed significant associations between USP8 Mutations and larger tumors in between CDKN1A Mutations and silent tumors.
The only CNV abnormality common to all tumor types was the acquisition of genetic material in a specific DNA region of chromosome 10 called 10q11.22.
Remarkably, amplification of a specific region of DNA called 17q12 was found in ACTH-producing adenomas that cause Cushing’s, all SCAs, and CCAs, “highlighting their benign nature” relative to the carcinoid tumor, the team wrote.
The team then performed a further analysis of the hypothetical step-down transformation of an SCA into an ACTH-producing adenoma, and finally into an ACTH-producing carcinoma.
They found that a specific mutation in ATF7IP The gene (p.K529R) may be involved in the transition from SCA to functional pituitary adenoma. In addition, there is a specific mutation in MSH3 The gene (p.I79V) may be required for ACTH-causing Cushing’s adenoma to develop 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 association with pituitary adenomas.
These results highlight that “ACTH-secreting functioning lesions have a higher number of SNVs and CNVs than non-functioning ACTH-secreting adenomas,” and that “ACTH-secreting adenomas [carcinoma] It shows more genomic abnormalities than other pests, confirming 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 findings. The scientists noted that future research is needed to understand the role of these genetic changes in pituitary adenomas.