Genetic and epigenetic mechanisms of tumorigenesis in Lynch and Lynch-like Syndrome

Noora Porkka

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma


Lynch syndrome is the most prevalent cancer predisposition syndrome that causes significantly increased lifetime risk of cancer in multiple organs such as colorectum, endometrium and ovarium. The predisposition is caused by germline mutations in DNA mismatch repair (MRR) genes MLH1, MSH2, MSH6, and PMS2. Lynch-like syndrome colorectal tumors, like Lynch syndrome tumors, are MMR-deficient. Nevertheless, Lynch-like syndrome tumors do not bear germline mutations in MMR genes nor methylation of the promoter regions of MMR genes that would explain the deficiency. Instead, MMR deficiency in majority of Lynch-like syndrome tumors is caused by two somatic mutations in the MMR genes. Dysfunctional MMR protein complex enables accumulation of mutations in the genome (mutator phenotype) and, eventually, microsatellite instability and cancer. The reasons behind organ selectivity in MMR-deficient tumors are unknown, and whether breast cancer is part of the Lynch syndrome spectrum is under debate. The germline mutations in MMR genes are well studied, but molecular characteristics of Lynch syndrome tumors remain to be studied further. Lynch-like syndrome tumors remain less well characterized: besides the double somatic MMR mutations as a cause of MMR deficiency, their molecular and clinicopathological features as well as their incidence in the population remain poorly known. Currently, the only possibility to diagnose Lynch-like syndrome is by ruling out the possibility of germline mutations in MMR genes (Lynch syndrome) or methylation of the promoter regions of MMR genes. Synchronous ovarian and endometrial carcinomas are common in Lynch syndrome; whether they are of same origin (metastatic cancer) or two independently developed primary cancers remains to be resolved. We aimed to characterize the epigenetic and somatic mutation profiles in Lynch syndrome representing colorectal, ovarian, endometrial and breast carcinomas, and to identify new unique features that could be used in evaluating cancer risk, diagnosis and targeted treatment. We used targeted high-throughput sequencing of 578 known cancer genes to investigate the somatic mutation profiles, and methylation-specific multiplex ligation-dependent probe amplification to study the epigenetic profiles of the tumors. Non-synonymous somatic mutations were detected from sequencing data of the paired tumor and normal tissues to determine mutation signatures and identify potential driver genes. The data was also compared statistically between tumors of different origin, epigenetic status, and between breast carcinomas from Lynch syndrome mutation carriers and their known non-carrier family members. We observed that Lynch- and Lynch-like syndrome tumors have unique somatic mutation and methylation profiles. We were able to link the methylator phenotype to high somatic mutation rates, and Lynch-like colorectal tumors to hypermethylated CpG island methylator phenotype (CIMP), which are novel findings. Our discovery of high mutation burden in genes associated with epigenetic regulation provides a new link between genetic and epigenetic factors in tumorigenesis. Genetic and epigenetic characterization of synchronous ovarian and endometrial carcinomas indicated shared origin, in analogy to sporadic cases. Molecular characteristics and especially mutational signatures of breast tumors of Lynch syndrome mutation carriers indicated that breast carcinoma is likely to be part of the Lynch syndrome tumor spectrum. These findings bear potential clinical relevance since the molecular tumor profiles may be used in diagnosis and may guide tailored management of the patients. Many of the mutated genes are part of signaling routes to which targeted molecules either exist or can be developed.
  • Peltomäki, Päivi T, Valvoja
  • Nieminen, Taina, Valvoja
Painoksen ISBN978-951-51-5928-1
Sähköinen ISBN978-951-51-5929-8
TilaJulkaistu - 2020
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)


  • 3111 Biolääketieteet

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