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Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma
Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden.
Division of Oncology, Department of Clinical Sciences Lund, Lund University, Sweden ; Lund University Cancer Centre (LUCC), Lund University, Sweden.
Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden.
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2024 (English)In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, article id deae043Article in journal (Refereed) Epub ahead of print
Abstract [en]

STUDY QUESTION: Can the alleged association between ovarian endometriosis and ovarian carcinoma be substantiated by genetic analysis of endometriosis diagnosed prior to the onset of the carcinoma?

SUMMARY ANSWER: The data suggest that ovarian carcinoma does not originate from ovarian endometriosis with a cancer-like genetic profile; however, a common precursor is probable.

WHAT IS KNOWN ALREADY: Endometriosis has been implicated as a precursor of ovarian carcinoma based on epidemiologic studies and the discovery of common driver mutations in synchronous disease at the time of surgery. Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are the most common endometriosis-associated ovarian carcinomas (EAOCs).

STUDY DESIGN, SIZE, DURATION: The pathology biobanks of two university hospitals in Sweden were scrutinized to identify women with surgically removed endometrioma who subsequently developed ovarian carcinoma (1998-2016). Only 45 archival cases with EAOC and previous endometriosis were identified and after a careful pathology review, 25 cases were excluded due to reclassification into non-EAOC (n = 9) or because ovarian endometriosis could not be confirmed (n = 16). Further cases were excluded due to insufficient endometriosis tissue or poor DNA quality in either the endometriosis, carcinoma, or normal tissue (n = 9). Finally 11 cases had satisfactory DNA from all three locations and were eligible for further analysis.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Epithelial cells were collected from formalin-fixed and paraffin-embedded (FFPE) sections by laser capture microdissection (endometrioma n = 11) or macrodissection (carcinoma n = 11) and DNA was extracted. Normal tissue from FFPE sections (n = 5) or blood samples collected at cancer diagnosis (n = 6) were used as the germline controls for each included patient. Whole-exome sequencing was performed (n = 33 samples). Somatic variants (single-nucleotide variants, indels, and copy number alterations) were characterized, and mutational signatures and kataegis were assessed. Microsatellite instability and mismatch repair status were confirmed with PCR and immunohistochemistry, respectively.

MAIN RESULTS AND THE ROLE OF CHANCE: The median age for endometriosis surgery was 42 years, and 54 years for the subsequent ovarian carcinoma diagnosis. The median time between the endometriosis and ovarian carcinoma was 10 (7-30) years. The data showed that all paired samples harbored one or more shared somatic mutations. Non-silent mutations in cancer-associated genes were frequent in endometriosis; however, the same mutations were never observed in subsequent carcinomas. The degree of clonal dominance, demonstrated by variant allele frequency, showed a positive correlation with the time to cancer diagnosis (Spearman's rho 0.853, P < 0.001). Mutations in genes associated with immune escape were the most conserved between paired samples, and regions harboring these genes were frequently affected by copy number alterations in both sample types. Mutational burdens and mutation signatures suggested faulty DNA repair mechanisms in all cases.

LARGE SCALE DATA: Datasets are available in the supplementary tables.

LIMITATIONS, REASONS FOR CAUTION: Even though we located several thousands of surgically removed endometriomas between 1998 and 2016, only 45 paired samples were identified and even fewer, 11 cases, were eligible for sequencing. The observed high level of intra- and inter-heterogeneity in both groups (endometrioma and carcinoma) argues for further studies of the alleged genetic association.

WIDER IMPLICATIONS OF THE FINDINGS: The observation of shared somatic mutations in all paired samples supports a common cellular origin for ovarian endometriosis and ovarian carcinoma. However, contradicting previous conclusions, our data suggest that cancer-associated mutations in endometriosis years prior to the carcinoma were not directly associated with the malignant transformation. Rather, a resilient ovarian endometriosis may delay tumorigenesis. Furthermore, the data indicate that genetic alterations affecting the immune response are early and significant events.

STUDY FUNDING/COMPETING INTEREST(S): The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE-A Strategic Research Area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad's Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden's Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021-01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.). A.S. declares stock ownership and is also a board member in Tulebovaasta, SiMSen Diagnostics, and Iscaff Pharma. A.S. has also received travel support from EMBL, Precision Medicine Forum, SLAS, and bioMCC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Place, publisher, year, edition, pages
Oxford University Press, 2024. article id deae043
Keywords [en]
clear cell ovarian carcinoma, copy number alteration, endometrioid ovarian carcinoma, exome-sequencing, mutation, ovarian endometriosis
National Category
Cancer and Oncology
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:his:diva-23673DOI: 10.1093/humrep/deae043ISI: 001181452700001PubMedID: 38459814OAI: oai:DiVA.org:his-23673DiVA, id: diva2:1846320
Funder
Sjöberg Foundation, 2021-01145Sjöberg Foundation, 2022-01-11:4Swedish Cancer Society, 21-1848Swedish Cancer Society, 21-1684Swedish Cancer Society, 22-2080Mrs. Berta Kamprad's Cancer Foundation, FBKS-2019-28Cancer and Allergy Foundation, 10381Region Västra GötalandVinnova, 2020-04141Swedish Research Council, 2021- 01008Stiftelsen Assar Gabrielssons fond, FB19-86
Note

CC BY-NC 4.0 Deed

Correspondence address.

Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academyat University of Gothenburg, SE-405 30 Gothenburg, Sweden. E-mail: karin.sundfeldt@gu.se (K.S.) https://orcid.org/0000-0002-7135-3132;

Division of Oncology,Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden. E-mail: ingrid.hedenfalk@med.lu.se (I.H.) https://orcid.org/0000-0002-6840-3

The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE—a strategic research area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad’s Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden’s Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021- 01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.).

Available from: 2024-03-22 Created: 2024-03-22 Last updated: 2024-04-15Bibliographically approved

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