From the Guidelines
The GUST/PAX8 gene is primarily associated with thyroid development and function, as well as certain thyroid cancers, including follicular thyroid carcinoma and papillary thyroid carcinoma, where it has been implicated through molecular testing for thyroid nodules, such as PAX8/PPARγ mutations 1.
Key Associations of GUST/PAX8 Gene
- Thyroid development and function: The gene plays a crucial role in the formation of the thyroid gland during embryonic development and continues to regulate thyroid-specific genes in adults.
- Congenital hypothyroidism: Mutations in PAX8 are associated with this condition, characterized by inadequate thyroid hormone production from birth.
- Thyroid cancers: Abnormal expression or function of PAX8 can contribute to malignant transformation, particularly in follicular thyroid carcinoma and papillary thyroid carcinoma.
- Kidney tissues: PAX8 is also expressed in kidney tissues and has been linked to certain renal conditions.
Molecular Testing and Diagnosis
Molecular testing for thyroid nodules, including testing for PAX8/PPARγ mutations, has been shown to be a strong indicator of cancer, with approximately 97% of mutation-positive nodules having a malignant diagnosis at histology 1. This highlights the importance of PAX8 in the diagnosis and potentially in the management of thyroid cancers.
From the Research
GUST/PAX8 Gene Association
The GUST/PAX8 gene is associated with various epithelial neoplasms, including:
- Renal epithelial neoplasms, such as clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, and renal oncocytoma 2, 3
- Thyroid gland carcinomas, including follicular, papillary, and anaplastic thyroid carcinomas 4, 5
- Müllerian duct-related carcinomas, such as ovarian and endometrial carcinomas 4
- Thymic epithelial neoplasms, including thymic carcinomas and thymomas 5
Expression and Diagnostic Utility
PAX8 expression has been detected in a high percentage of these tumors, making it a valuable diagnostic marker:
- PAX8 is expressed in 93% of clear cell renal cell carcinomas, 80% of chromophobe renal cell carcinomas, 95% of papillary renal cell carcinomas, and 94% of renal oncocytomas 2
- PAX8 is also expressed in thymic epithelial neoplasms, with positive immunoreactivity noted in 77% of thymic carcinomas, 100% of WHO type A thymomas, and 93% of WHO type B thymomas 5
- PAX8 expression can be used to differentiate between primary and metastatic tumors, with PAX8 staining noted in more cells and with more intense staining than PAX2 3
Oncogenic Signalling and Tissue-Specific Cancer Risk
The PAX8 gene plays a crucial role in oncogenic signalling and tissue-specific cancer risk:
- PAX8 is required for oncogenic signalling by common genetic alterations that cause clear cell renal cell carcinoma, including the germline variant rs7948643 and somatic inactivation of the von Hippel-Lindau tumour suppressor 6
- PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 enhancer, are preferentially recruited by HIF2A, leading to downstream activation of CCND1 expression 6