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FältnamnIndikatorerMetadata
00014039naa a2200721 4500
001oai:DiVA.org:his-23673
003SwePub
008240322s2024 | |||||||||||000 ||eng|
009oai:gup.ub.gu.se/335992
009oai:lup.lub.lu.se:0171cf11-9812-4028-9c06-5ec71f08be6b
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-236732 URI
0247 a https://doi.org/10.1093/humrep/deae0432 DOI
0247 a https://gup.ub.gu.se/publication/3359922 URI
0247 a https://lup.lub.lu.se/record/0171cf11-9812-4028-9c06-5ec71f08be6b2 URI
040 a (SwePub)hisd (SwePub)gud (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Linder, Annau University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi,Institute of Clinical Sciences, Department of Obstetrics and Gynecology,Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden4 aut0 (Swepub:gu)xliana
2451 0a Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma
264 1b Oxford University Press,c 2024
338 a electronic2 rdacarrier
500 a CC BY-NC 4.0 DeedPublished: 09 March 2024Correspondence address: Karin Sundfeldt, 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/0000-0002-6840-3The 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.).
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Reproduktionsmedicin och gynekologi0 (SwePub)302202 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Obstetrics, Gynaecology and Reproductive Medicine0 (SwePub)302202 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Medicinsk genetik0 (SwePub)301072 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medical Genetics0 (SwePub)301072 hsv//eng
653 a clear cell ovarian carcinoma
653 a copy number alteration
653 a endometrioid ovarian carcinoma
653 a exome-sequencing
653 a mutation
653 a ovarian endometriosis
653 a Bioinformatik
653 a Bioinformatics
653 a ovarian endometriosis
653 a clear cell ovarian carcinoma
653 a endometrioid ovarian carcinoma
653 a exome-sequencing
653 a mutation
653 a copy number alteration
7001 a Westbom-Fremer, Su Lund University,Lunds universitet,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breast and Ovarian Cancer Genomics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments4 aut0 (Swepub:lu)so4231we
7001 a Mateoiu, C.u Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden4 aut
7001 a Olsson Widjaja, Amanda,d 1991u University of Gothenburg,Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi,Sahlgrenska Center for Cancer Research (SCCR),Institute of Clinical Sciences, Department of Obstetrics and Gynecology,Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden4 aut0 (Swepub:gu)xoaman
7001 a Österlund, Tobias,d 1984u University of Gothenburg,Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden ; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden4 aut0 (Swepub:gu)xsteto
7001 a Veerla, Su Lund University,Lunds universitet,Forskningsgrupp Lungcancer,Forskargrupper vid Lunds universitet,Bröst- och ovarialcancer,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Bröst/lungcancer,Research Group Lung Cancer,Lund University Research Groups,Breast and Ovarian Cancer Genomics,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Breast/lung cancer4 aut0 (Swepub:lu)klin-sve
7001 a Ståhlberg, Anders,d 1975u University of Gothenburg,Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för biomedicin, avdelningen för laboratoriemedicin,Sahlgrenska Center for Cancer Research (SCCR),Department of Laboratory Medicine,Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden ; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sweden4 aut0 (Swepub:gu)xsandw
7001 a Ulfenborg, Benjamin,d 1985-u University of Skövde,Högskolan i Skövde,Institutionen för biovetenskap,Forskningsmiljön Systembiologi,Translationell bioinformatik, Translational Bioinformatics4 aut0 (Swepub:his)ulfb
7001 a Hedenfalk, Iu Lund University,Lunds universitet,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breast and Ovarian Cancer Genomics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments4 aut0 (Swepub:lu)onk-ifa
7001 a Sundfeldt, Karin,d 1962u University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Clinical Sciences, Department of Obstetrics and Gynecology,Sahlgrenska Center for Cancer Research (SCCR),Department of Obstetrics and Gynecology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sweden ; Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden4 aut0 (Swepub:gu)xsukar
7102 a Göteborgs universitetb Institutionen för kliniska vetenskaper, Avdelningen för obstetrik och gynekologi4 org
7730 t Human Reproductiond : Oxford University Pressg 39:5, s. 1141-1154q 39:5<1141-1154x 0268-1161x 1460-2350
8564 u https://doi.org/10.1093/humrep/deae043y Fulltext
8564 u https://his.diva-portal.org/smash/get/diva2:1846320/FULLTEXT02.pdfx primaryx Raw objecty fulltext:print
8564 u http://dx.doi.org/10.1093/humrep/deae043x freey FULLTEXT
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-23673
8564 8u https://doi.org/10.1093/humrep/deae043
8564 8u https://gup.ub.gu.se/publication/335992
8564 8u https://lup.lub.lu.se/record/0171cf11-9812-4028-9c06-5ec71f08be6b

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