A1 Journal article (refereed)
Does breast carcinoma belong to the Lynch syndrome tumor spectrum? : Somatic mutational profiles vs. ovarian and colorectal carcinomas (2020)

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

JYU authors or editors

Publication details

All authors or editors: Porkka, Noora K.; Olkinuora, Alisa; Kuopio, Teijo; Ahtiainen, Maarit; Eldfors, Samuli; Almusa, Henrikki; Mecklin, Jukka-Pekka; Peltomäki, Päivi

Journal or series: Oncotarget

eISSN: 1949-2553

Publication year: 2020

Volume: 11

Issue number: 14

Pages range: 1244-1256

Publisher: Impact Journals LLC

Publication country: United States

Publication language: English

DOI: https://doi.org/10.18632/oncotarget.27538

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/68672

Abstract

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.

Keywords: cancerous diseases; hereditary diseases; Lynch syndrome; breast cancer; oncogenes; mutations

Free keywords: Lynch syndrome; breast carcinoma; MSI; DNA mismatch repair; somatic mutation

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2020

JUFO rating: 0