Does breast carcinoma belong to the Lynch syndrome tumor spectrum? : Somatic mutational profiles vs. ovarian and colorectal carcinomas
Porkka, N. K., Olkinuora, A., Kuopio, T., Ahtiainen, M., Eldfors, S., Almusa, H., Mecklin, J.-P., & Peltomäki, P. (2020). Does breast carcinoma belong to the Lynch syndrome tumor spectrum? : Somatic mutational profiles vs. ovarian and colorectal carcinomas. Oncotarget, 11(14), 1244-1256. https://doi.org/10.18632/oncotarget.27538
Julkaistu sarjassa
OncotargetTekijät
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2020Tekijänoikeudet
© Porkka et al.
Inherited DNA mismatch repair (MMR) defects cause predisposition to colorectal, endometrial, ovarian, and other cancers occurring in Lynch syndrome (LS). It is unsettled whether breast carcinoma belongs to the LS tumor spectrum. We approached this question through somatic mutational analysis of breast carcinomas from LS families, using established LS-spectrum tumors for comparison. Somatic mutational profiles of 578 cancer-relevant genes were determined for LS-breast cancer (LS-BC, n = 20), non-carrier breast cancer (NC-BC, n = 10), LS-ovarian cancer (LS-OC, n = 16), and LS-colorectal cancer (LS-CRC, n = 18) from the National LS Registry of Finland. Microsatellite and MMR protein analysis stratified LS-BCs into MMR-deficient (dMMR, n = 11) and MMR-proficient (pMMR, n = 9) subgroups. All NC-BCs were pMMR and all LS-OCs and LS-CRCs dMMR. All but one dMMR LS-BCs were hypermutated (> 10 non-synonymous mutations/Mb; average 174/Mb per tumor) and the frequency of MMR-deficiency-associated signatures 6, 20, and 26 was comparable to that in LS-OC and LS-CRC. LS-BCs that were pMMR resembled NC-BCs with respect to somatic mutational loads (4/9, 44%, hypermutated with average mutation count 33/Mb vs. 3/10, 30%, hypermutated with average 88 mutations/Mb), whereas mutational signatures shared features of dMMR LS-BC, LS-OC, and LS-CRC. Epigenetic regulatory genes were significantly enriched as mutational targets in LS-BC, LS-OC, and LS-CRC. Many top mutant genes of our LS-BCs have previously been identified as drivers of unselected breast carcinomas. In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS.
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https://converis.jyu.fi/converis/portal/detail/Publication/35267030
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This work was supported by Jane and Aatos Erkko Foundation (to P.P. and J.-P.M); the Academy of Finland (grant number 294643 to P.P); the Finnish Cancer Foundation (to N.P, P.P., and J.-P.M); the Sigrid Juselius Foundation (to P.P); the HiLIFE Fellows 2017–2020 (to P.P); K. Albin Johansson Stiftelse (to N.P).Lisenssi
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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment : a report from the prospective Lynch syndrome database
Dominguez-Valentin, Mev; Haupt, Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone; Bernstein, Inge; Jenkins, Mark A.; Engel, Christoph; Aretz, Stefan; Nielsen, Maartje; Capella, Gabriel; Balaguer, Francesc; Evans, Dafydd Gareth; Burn, John; Holinski-Feder, Elke; Bertario, Lucio; Bonanni, Bernardo; Lindblom, Annika; Levi, Zohar; Macrae, Finlay; Winship, Ingrid; Plazzer, John-Paul; Sijmons, Rolf; Laghi, Luigi; Della Valle, Adriana; Heinimann, Karl; Dębniak, Tadeusz; Fruscio, Robert; Lopez-Koestner, Francisco; Alvarez-Valenzuela, Karin; Katz, Lior H.; Laish, Ido; Vainer, Elez; Vaccaro, Carlos; Carraro, Dirce Maria; Monahan, Kevin; Half, Elizabeth; Stakelum, Aine; Winter, Des; Kennelly, Rory; Gluck, Nathan; Sheth, Harsh; Abu-Freha, Naim; Greenblatt, Marc; Rossi, Benedito Mauro; Bohorquez, Mabel; Cavestro, Giulia Martina; Lino-Silva, Leonardo S.; Horisberger, Karoline; Tibiletti, Maria Grazia; do Nascimento, Ivana; Thomas, Huw; Rossi, Norma Teresa; Apolinário da Silva, Leandro; Zaránd, Attila; Ruiz-Bañobre, Juan; Heuveline, Vincent; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Peltomäki, Päivi; Therkildsen, Christina; Madsen, Mia Gebauer; Burgdorf, Stefan Kobbelgaard; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane; Buchanan, Daniel D.; Thibodeau, Stephen N.; von Knebel Doeberitz, Magnus; Loeffler, Markus; Rahner, Nils; Schröck, Evelin; Steinke-Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Hüneburg, Robert; Redler, Silke; Büttner, Reinhard; Weitz, Jürgen; Pineda, Marta; Duenas, Nuria; Vidal, Joan Brunet; Moreira, Leticia; Sánchez, Ariadna; Hovig, Eivind; Nakken, Sigve; Green, Kate; Lalloo, Fiona; Hill, James; Crosbie, Emma; Mints, Miriam; Goldberg, Yael; Tjandra, Douglas; ten Broeke, Sanne W.; Kariv, Revital; Rosner, Guy; Advani, Suresh H.; Thomas, Lidiya; Shah, Pankaj; Shah, Mithun; Neffa, Florencia; Esperon, Patricia; Pavicic, Walter; Torrezan, Giovana Tardin; Bassaneze, Thiago; Martin, Claudia Alejandra; Moslein, Gabriela; Moller, Pål (Elsevier BV, 2023)Background The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, ... -
Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort
Sipilä, Lauri J.; Aavikko, Mervi; Ravantti, Janne; Martin, Samantha; Kuopio, Teijo; Lahtinen, Laura; FinnGen; Peltomäki, Päivi; Mecklin, Jukka-Pekka; Aaltonen, Lauri A.; Seppälä, Toni T. (Springer, 2024)Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in MLH1, in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a ... -
The “unnatural” history of colorectal cancer in Lynch syndrome : lessons from colonoscopy surveillance
Ahadova, Aysel; Seppälä, Toni T.; Engel, Christoph; Gallon, Richard; Burn, John; Holinski‐Feder, Elke; Steinke‐Lange, Verena; Möslein, Gabriela; Nielsen, Maartje; ten Broeke, Sanne; Laghi, Luigi; Dominguez‐Valentin, Mev; Capella, Gabriel; Macrae, Finlay; Scott, Rodney; Hüneburg, Robert; Nattermann, Jacob; Hoffmeister, Michael; Brenner, Hermann; Bläker, Hendrik; von Knebel Doeberit,z Magnus; Sampson, Julian R.; Vasen, Hans; Mecklin, Jukka‐Pekka; Møller, Pål; Kloor, Matthias (Wiley, 2021)Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is ... -
Converging endometrial and ovarian tumorigenesis in Lynch syndrome : shared origin of synchronous carcinomas
Niskakoski, Anni; Pasanen, Annukka; Porkka, Noora; Eldfors, Samuli; Lassus, Heini; Renkonen-Sinisalo, Laura; Kaur, Sippy; Mecklin, Jukka-Pekka; Bützowb, Ralf; Peltomäki, Päivi (Academic Press, 2018)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 ... -
Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report
Seppälä, Toni T.; Ahadova, Aysel; Dominguez-Valentin, Mev; Macrae, Finlay; Evans, D. Gareth; Therkildsen, Christina; Sampson, Julian; Scott, Rodney; Burn, John; Möslein, Gabriela; Bernstein, Inge; Holinski-Feder, Elke; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Lautrup, Charlotte Kvist; Lindblom, Annika; Plazzer, John-Paul; Winship, Ingrid; Tjandra, Douglas; Katz, Lior H.; Aretz, Stefan; Hüneburg, Robert; Holzapfel, Stefanie; Heinimann, Karl; Valle, Adriana Della; Neffa, Florencia; Gluck, Nathan; Cappel, Wouter H. de Vos tot Nederveen; Vasen, Hans; Morak, Monika; Steinke-Lange, Verena; Engel, Christoph; Rahner, Nils; Schmiegel, Wolff; Vangala, Deepak; Thomas, Huw; Green, Kate; Lalloo, Fiona; Crosbie, Emma J.; Hill, James; Capella, Gabriel; Pineda, Marta; Navarro, Matilde; Blanco, Ignacio; Broeke, Sanne ten; Nielsen, Maartje; Ljungmann, Ken; Nakken, Sigve; Lindor, Noralane; Frayling, Ian; Hovig, Eivind; Sunde, Lone; Kloor, Matthias; Mecklin, Jukka-Pekka; Kalager, Mette; Møller, Pål (BioMed Central Ltd., 2019)Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. ...
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