Public PhD defence
Mariann Kasela, M.Sc. defended the doctoral dissertation entitled "Reduced mismatch repair gene expression and functional deficiency as indicators of Lynch syndrome".


Lynch syndrome (LS, also known as HNPCC) is an inherited cancer predisposition syndrome caused by DNA mismatch repair (MMR) malfunction. Cancer predisposition in Lynch syndrome is autosomal dominantly inherited through one defective MMR gene (MLH1, MSH2, MSH6, PMS2) allele. Tumorigenesis starts after somatic loss of the second allele, giving rise most commonly to early-onset colorectal and endometrial cancers, and more rarely cancers of the uterine, stomach, urinary tract, ovary, small intestine or bile tract. Early diagnosis of LS is important, since clinical surveillance and prophylactic surgeries significantly reduce cancer-related mortality in MMR gene mutation carriers. The diagnosis is based on cancer history of the family and on tumor studies, followed by genetic testing to determine a predisposing mutation. However, the atypical clinical phenotypes such as late age at onset, lower penetrance and different tumor spectrums associated with some families, as well as the increasing number of variants of uncertain significance (VUS) found in sequencing, complicate LS diagnosis and highlight the need for pathogenicity assessment.

In her thesis Mariann Kasela studied the functional effect of lowered MMR gene expression as an indication of Lynch syndrome and assessed the pathogenicity of MMR gene variants of uncertain clinical significance. With the help of a stable shRNA knockdown approach, and an in vitro MMR assay she studied how decreased MLH1, MSH2, MSH6 and PMS2 gene expression levels affect MMR efficiency. The results showed that the repair efficiency of MMR protein was associated with the respective gene´s expression level of majority of the genes. Furthermore, the decrease in gene expression had different effects on the repair ability of different proteins. At the second part of her thesis, the functional significance of five MLH1 and four MSH2 VUSs found in suspected LS families was determined by the in vitro MMR assay. Her results, together with the clinical and tumor data collected from the families, allowed the pathogenicity assessment of the MMR gene variants and Lynch syndrome diagnosis in the families.

Mariann Kasela, M.Sc. defended the doctoral dissertation entitled "Reduced mismatch repair gene expression and functional deficiency as indicators of Lynch syndrome" in the Faculty of Biological and Environmental Sciences, University of Helsinki, on 26 June 2020. 

Professor Karl Heinimann, University of Basel, Switzerland, served as the opponent, and Professor Minna Nyström as the custos.

The dissertation is available in electronic form through the E-thesis service.