Targeted next-generation sequencing for the detection of cancer-associated somatic mutations in adenomyosis

Abstract

Adenomyosis is a condition characterised by the invasion of endometrial tissues into the uterine myometrium, the molecular pathogenesis of which remains incompletely elucidated. Lesion profiling with next-generation sequencing (NGS) can lead to the identification of previously unanticipated causative genes and the detection of therapeutically actionable genetic changes. Using an NGS panel that included 275 cancer susceptibility genes, this study examined the occurrence and frequency of somatic mutations in adenomyotic tissue specimens collected from 17 women. Extracted DNA was enriched using targeted formalin-fixed paraffin-embedded tissue cores prior to the identification of lesion-specific variants. The results revealed that KRAS and AT-rich interactive domain 1A (ARID1A) were the two most frequently mutated genes (mutation frequencies: 24% and 12%, respectively). Notably, endometrial atypical hyperplasia did not involve adenomyotic areas. We also identified, for the first time, two potentially pathogenic mutations in the F-box/WD repeat-containing protein 7 (FBXW7) and cohesin subunit SA-2 (STAG2) genes. These findings indicate that mutations in the KRAS, ARID1A, FBXW7 and STAG2 genes may play a critical role in the pathogenesis of adenomyosis. Additional studies are needed to assess whether the utilisation of oncogenic driver mutations can inform the surveillance of patients with adenomyosis who had not undergone hysterectomy.

Impact statement

• What is already known on this subject? Although somatic point mutations in the KRAS oncogene have been recently detected in adenomyosis, the molecular underpinnings of this condition remains incompletely elucidated. Lesion profiling with next-generation sequencing (NGS) can lead to the identification of previously unanticipated causative genes and the detection of therapeutically actionable genetic changes.

• What do the results of this study add? The results of NGS revealed that KRAS and AT-rich interactive domain 1A (ARID1A) were the two most frequently mutated genes (mutation frequencies: 24% and 12%, respectively). We also identified, for the first time, two potentially pathogenic mutations in the F-box/WD repeat-containing protein 7 (FBXW7) and cohesin subunit SA-2 (STAG2) genes.

• What are the implications of these findings for clinical practice and/or further research? The utilisation of oncogenic driver mutations has the potential to inform the surveillance of patients with adenomyosis who had not undergone hysterectomy.

Keywords:

• Adenomyosis
• next-generation sequencing
• KRAS
• ARID1A
• FBXW7
• STAG2

Acknowledgements

We thank Jung-Erh Yang and Chu-Chun Huang for their excellent technical assistance. We are also grateful to the NGS Core Lab of the Molecular Medicine Research Centre at the Chang Gung University.

Author contributions

A.C. and C.J.W.: study conception and design; A.C., R.C.W., C.Y.L. and C.J.W.: drafting the manuscript or revising it critically for important intellectual content; R.C.W., C.Y.L. and C.L.T.: acquisition, analysis and interpretation of data; Y.S.L.: study supervision, critical revision of the manuscript for important intellectual content. All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, have been involved in drafting the manuscript or revising it critically for important intellectual content, have given final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure statement

The authors declare that they have no conflicts of interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This research was financially supported by grants (CMRPG3G2001, CMRPG3J1491, CMRPG3H1153 and CSRPG3J0011) from the Chang Gung Foundation.