Abstract LB-375: The landscape of somatic mutations in uterine adenomyomas
Authors: Tolvanen Jaana , Heinonen Hanna-Riikka , Sarvilinna Nanna , Sjöberg Jari , Heikinheimo Oskari , Pasanen Annukka , Bützow Ralf , Aaltonen Lauri A. , Mäkinen Netta 
Published: August 2018

Uterine adenomyosis is a relatively common disorder characterized by the abnormal presence of endometrial glands and stroma in the myometrium. The estimated prevalence of adenomyosis varies between 20-30% in hysterectomy specimens. Approximately 65% of the patients develop symptoms, including dysmenorrhea and heavy menstrual bleeding. Additionally, adenomyosis has been shown to significantly associate with peritoneal endometriosis in infertile patients. A circumscribed and nodular form of adenomyosis is called an adenomyoma (AM). This lesion is often misdiagnosed as uterine leiomyoma (ULM), a benign smooth muscle tumor of the uterus. To date, the molecular mechanisms underlying adenomyosis are rather poorly understood. The aim of this study was to investigate the molecular genetic background of uterine AMs by whole-exome sequencing, as well as to examine if the known ULM driver changes play a role in the genesis of AMs.

This study focused on patients with nodular uterine AMs. A total of 16 AMs and matched normal myometrium samples from 14 hysterectomy patients entered exome sequencing.  From each lesion, genomic DNA was extracted separately from both the myometrial and endometrial components. Coding regions were enriched using SeqCap EZ System (Roche Nimblegen) and sequencing was performed with Illumina HiSeq 4000. Comprehensive clinical information was available for 13 out of 14 patients.

The average age at diagnosis was 45 years and at hysterectomy 49 years among patients. All patients had experienced dysmenorrhea (9/13, 69%), heavy menstrual bleeding (10/13, 77%), or both as symptoms. Endometriosis had been diagnosed in 62% (8/13) and infertility in 15% (2/13) of the patients. ULMs occurred in 8/14 (57%) patients. The average coverage of exome sequencing data was 44x for AMs. In each sample, 85% of targeted bases were covered with at least 10 reads. After filtering out germline variation, all AM samples displayed, on average, 16 somatic variants. The most prominent variants are validated in a set of additional adenomyosis samples.

Based on our results, the genetic background of AMs differs from that of ULMs due to the lack of ULM driver changes: MED12 mutations, HMGA2 overexpression, and biallelic FH inactivation. Only one AM had a somatic missense mutation in MED12, and no HMGA2 overexpression was detected. Studies on FH inactivation are still ongoing. Knowledge of the molecular background of AMs is important for understanding the development of the condition and essential for improving the management of these lesions. This is the first exome sequencing study to our knowledge to comprehensively profile somatic variation in uterine AMs.

Citation Format: Jaana Tolvanen, Hanna-Riikka Heinonen, Nanna Sarvilinna, Jari Sjöberg, Oskari Heikinheimo, Annukka Pasanen, Ralf Bützow, Lauri A. Aaltonen, Netta Mäkinen. The landscape of somatic mutations in uterine adenomyomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-375.