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AXIN genetic analysis in adrenocortical carcinomas updated
A Guimier1, B Ragazzon, G Assié
1Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Background:
Wnt/β-catenin signaling pathway activation plays an important role in adrenocortical tumorigenesis, but is only in part related to β-catenin activating somatic mutations. Recently, genetic alteration in AXIN2, a key component of the Wnt/β-catenin signaling pathway, has been described in adrenocortical tumors and specifically in adrenocortical carcinoma (ACC).
Aim:
To assess frequency and consequences of AXIN genes alteration on a large cohort of ACC.
Patients And Methods:
Forty-nine adult sporadic ACC, with expression data available, in addition to both ACC cell lines H295 and H295R were studied. AXIN2 exon 8 hot-spot sequencing was performed on the entire cohort. AXIN1 entire coding region was studied on the 8 ACC with nuclear β-catenin staining.
Results:
The previously described AXIN2 in-frame heterozygous 12bp deletion c2013_2024del12 was found in 1 of the 49 ACC studied (2%), in a tumor with pSer45del activating CTNNB1 mutation and nuclear β-catenin staining. This heterozygous deletion was also found in the patient's germline DNA, extracted from peripheral blood leukocytes. This genetic alteration was also present in H295 and H295R cell lines. The single-nucleotide polymorphism rs35415678 was found with an allele frequency similar to those found in reference populations. No correlation between AXIN2 expression, AXIN2 genetic variant or nuclear β- catenin staining was observed. No AXIN1 alterations were found in the 8 ACC studied.
Conclusions:
AXIN genes do not play a major role in ACC tumorigenesis and Wnt/β-catenin signaling pathway activation. AXIN2 germline variant c2013_2024del12 is likely to be a non-pathogenic polymorphism.
Insights
Genetic alterations in AXIN genes are uncommon in adrenocortical carcinoma (ACC). The identified AXIN2 germline variant is likely a non-pathogenic polymorphism, suggesting AXIN genes do not significantly drive ACC tumorigenesis.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Wnt/β-catenin signaling is crucial in adrenocortical tumorigenesis, partly due to β-catenin mutations.
- Genetic alterations in AXIN2, a Wnt pathway component, have been noted in adrenocortical tumors, particularly ACC.
Purpose of the Study:
- To determine the frequency and impact of AXIN gene alterations in a large cohort of adrenocortical carcinoma (ACC) patients.
- To investigate the role of AXIN genes in ACC development and Wnt/β-catenin pathway activation.
Main Methods:
- Sequencing of AXIN2 exon 8 in 49 sporadic ACCs and AXIN1 in 8 ACCs with nuclear β-catenin.
- Analysis included ACC cell lines (H295, H295R) and patient germline DNA.
Main Results:
- A heterozygous AXIN2 deletion (c2013_2024del12) was found in 2% of ACCs, present in both tumor and germline DNA, and in cell lines.
- This deletion co-occurred with an activating CTNNB1 mutation and nuclear β-catenin.
- No correlation was found between AXIN2 expression, the genetic variant, or nuclear β-catenin. No AXIN1 alterations were detected.
Conclusions:
- AXIN genes do not appear to play a major role in adrenocortical carcinoma tumorigenesis or Wnt/β-catenin pathway activation.
- The AXIN2 germline variant c2013_2024del12 is likely a non-pathogenic polymorphism.
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