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Germline deletion and a somatic mutation of the PRKAR1A gene in a Carney complex-related pituitary adenoma
T Iwata1, T Tamanaha1, R Koezuka1
1Department of Medical PharmacologyInstitute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 3-18-15, Tokushima 770-8504, JapanDepartment of Endocrinology and MetabolismNational Cerebral and Cardiovascular Center, Osaka, JapanDepartments of PathologyHypothalamic and Pituitary SurgeryToranomon Hospital, Tokyo, JapanClinical Research InstituteNational Hospital Organization Kyoto Medical Center, Kyoto, Japan.
Objective:
The objective was to assess involvement of loss of the PRKAR1A gene encoding a type 1α regulatory subunit of cAMP-dependent protein kinase A located on 17q24 in a Carney complex (CNC)-related pituitary adenoma.
Design:
We investigated aberrations of the PRKAR1A gene in a CNC patient with a GH-producing pituitary adenoma, whose family has three other members with probable CNC.
Methods:
A gene mutation was identified by a standard DNA sequencing method based on PCR. DNA copy number was measured to evaluate allelic loss on 17q24 by quantitative PCR. The breakpoints of deletion were determined by cloning a rearranged region in the deleted allele.
Results:
A PRKAR1A mutation of c.751_758del8 (p.S251LfsX16) was found in genomic DNA obtained from a pituitary adenoma, but not leukocytes from the patient. Reduced DNA copy number at loci including the PRKAR1A gene on 17q24 was detected in both the tumor and leukocytes, suggesting a deletion at the loci at the germline level. The deletion size was determined to be ∼ 0.5 Mb and this large deletion was also found in two other family members.
Conclusion:
This is the first case showing a CNC-related pituitary adenoma with the combination of somatic mutation and a large inherited deletion of the PRKAR1A gene. Biallelic inactivation of PRKAR1A appears to be necessary for the development of CNC-related pituitary adenoma.
Insights
Carney complex (CNC)-related pituitary adenomas involve the PRKAR1A gene. This study found both a somatic mutation and inherited deletion of PRKAR1A in a patient, suggesting biallelic inactivation is necessary for tumor development.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Carney complex (CNC) is a rare genetic disorder associated with multiple tumors.
- Pituitary adenomas are a common manifestation of CNC.
- The PRKAR1A gene, encoding a regulatory subunit of protein kinase A, is frequently implicated in CNC.
Observation:
- A patient with a GH-producing pituitary adenoma and suspected CNC was investigated.
- The study examined aberrations in the PRKAR1A gene within the tumor and germline DNA.
- Genetic analysis included DNA sequencing and quantitative PCR to assess mutations and copy number variations.
Findings:
- A somatic mutation (c.751_758del8) in the PRKAR1A gene was identified in the pituitary adenoma, but not in the patient's leukocytes.
- A large (∼0.5 Mb) inherited deletion encompassing the PRKAR1A gene locus (17q24) was detected in the patient's tumor and leukocytes.
- This deletion was also present in two other family members with probable CNC.
Implications:
- This is the first report of a CNC-related pituitary adenoma with both a somatic PRKAR1A mutation and a large inherited deletion.
- Biallelic inactivation of the PRKAR1A gene appears to be a critical step in the pathogenesis of CNC-related pituitary adenomas.
- Understanding these genetic mechanisms can inform diagnosis and potential therapeutic strategies for CNC.
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