Anni Niskakoski1, Annukka Pasanen2, Noora Porkka3, Samuli Eldfors4, Heini Lassus5, Laura Renkonen-Sinisalo6, Sippy Kaur7, Jukka-Pekka Mecklin8, Ralf Bützow9, Päivi Peltomäki3. 1. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. Electronic address: anni.niskakoski@helsinki.fi. 2. Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Finland. 3. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 4. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 5. Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Finland. 6. Second Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland. 7. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Department of Oral and Maxillofacial diseases, University of Helsinki and Helsinki University Hospital, Finland. 8. Department of Surgery and Education & Science, Central Finland Health Care District, Finland; Department of Sport and Health Sciences, Jyväskylä University, Finland. 9. Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Finland; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Finland.
Abstract
OBJECTIVE: The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). METHODS: MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. RESULTS: Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. CONCLUSIONS: Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.
OBJECTIVE: The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). METHODS: MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. RESULTS:Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. CONCLUSIONS: Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.
Authors: Casper Reijnen; Heidi V N Küsters-Vandevelde; Marjolijn J L Ligtenberg; Johan Bulten; Marloes Oosterwegel; Marc P L M Snijders; Sanne Sweegers; Joanne A de Hullu; Maria C Vos; Anneke A M van der Wurff; Anne M van Altena; Astrid Eijkelenboom; Johanna M A Pijnenborg Journal: Int J Cancer Date: 2020-02-18 Impact factor: 7.396
Authors: Lea A Moukarzel; Arnaud Da Cruz Paula; Lorenzo Ferrando; Timothy Hoang; Ana Paula Martins Sebastiao; Fresia Pareja; Kay J Park; Achim A Jungbluth; Gabriel Capella; Marta Pineda; Jeffrey D Levin; Nadeem R Abu-Rustum; Lora H Ellenson; August Vidal Bel; Jorge S Reis-Filho; Xavier Matias-Guiu; Karen Cadoo; Zsofia K Stadler; Britta Weigelt Journal: Mod Pathol Date: 2020-12-16 Impact factor: 7.842