Research Papers:

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

Noora K. Porkka _, Alisa Olkinuora, Teijo Kuopio, Maarit Ahtiainen, Samuli Eldfors, Henrikki Almusa, Jukka-Pekka Mecklin and Päivi Peltomäki

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Oncotarget. 2020; 11:1244-1256. https://doi.org/10.18632/oncotarget.27538

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Noora K. Porkka1, Alisa Olkinuora1, Teijo Kuopio2,3, Maarit Ahtiainen4, Samuli Eldfors5, Henrikki Almusa5, Jukka-Pekka Mecklin6,7,8 and Päivi Peltomäki1

1 Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland

2 Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland

3 Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland

4 Department of Education and Research, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland

5 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

6 Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland

7 Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland

8 Department of Education & Science, Jyväskylä Central Hospital, Jyväskylä, Finland

Correspondence to:

Noora K. Porkka,email: [email protected]

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

Received: February 13, 2020     Accepted: March 14, 2020     Published: April 07, 2020


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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