Tumorigenesis in Lynch syndrome-associated breast carcinoma: profiles of somatic alterations compared with colorectal and ovarian carcinomas

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

1Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 2Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland. 3Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland. 4Department of Education and Research, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland. 5Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. 6Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 7Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland. 8Department of Education & Science, Jyväskylä Central Hospital, Jyväskylä, Finland



Germline mutations in one of four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause predisposition to Lynch syndrome (LS) tumors. It is debatable whether breast cancer is part of LS tumor spectrum. Moreover, the reasons for organ selectivity in germline mutation carriers are unknown.


The study includes 22 breast, 18 colorectal, and 16 ovarian carcinomas from LS patients, and 15 breast carcinomas from non-carriers. Tumors were studied for MMR status and DNA methylator phenotype. Panel sequencing (described in Porkka et al. 2017) was used to investigate the somatic mutation status. Mutational signature analysis was also performed for the somatic mutations.


Of 14 LS breast carcinoma samples studied so far, 9 (64 %) were MMR-deficient and 5 (36 %) MMR-proficient, compared with LS colorectal and ovarian carcinomas, all MMR-deficient (p=0.0012).  Detectable second hit was present in 43 % (6/14) of breast carcinomas, compared to the majority of LS colorectal and ovarian tumors (p=0.0025). Mutations in genes involved in epigenetic regulation were significantly enriched in all three tumor types, but a significant enrichment of mutated NOTCH signaling associated genes characterized LS breast carcinomas.


We demonstrate that breast carcinomas from LS patients have a unique molecular and somatic mutation profile. This research is likely to shed light to the mechanisms of organ-specific cancer susceptibility in germline carriers of MMR gene mutations. Our results are expected to guide the surveillance and other clinical management of LS individuals with breast carcinoma.

Abstract references

Porkka N, Valo S, Nieminen TT, Olkinuora A, Mäki-Nevala S, Eldfors S, Peltomäki P.

Oncotarget. 2017 Nov 14;8(64):108020-108030.