Virtanen, T. | Search bioRxiv

bioRxiv2024

Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer

Lynch syndrome (LS) is a hereditary condition characterized by defective DNA mismatch repair (MMR) and high incidence of several cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We set out to study the somatic landscape of LS-associated urothelial cancer (LS-UC) by analyzing 41 surgical tumor samples and 3 urine DNA samples from 34 LS-UC patients. We show that telomerase reverse transcriptase (TERT) promoter mutations found in 83% of sporadic UC are almost completely absent (5%) in LS-UC (p < 0.00001). Instead, all LS-UC carried a 5-methylcytosine deamination (CG>TG) and microsatellite instability driven mutation landscape characterized by highly frequent ARID1A (82%), FGFR3 (80%), and KMT2D (78%) mutations, as well as preferential usage of CG>TG mutation hotspots. We propose that the scarcity of TERT promoter mutations in LS-UC is due to inability to create the necessary GABP binding motif (5-GGAA) through CG>TG mutation or microsatellite instability. Our data shows that LS-UC represents a disease entity with unique genomic characteristics.

cancer biology↗

bioRxiv2019

Associations between neonatal cry acoustics and visual attention during the first year

It has been suggested that early cry parameters are connected to later cognitive abilities. The present study is the first to investigate whether the acoustic features of infant cry are associated with cognitive development already during the first year, as measured by oculomotor orienting and attention disengagement. Cry sounds for acoustic analyses (fundamental frequency; F0) were recorded in two neonatal cohorts at the age of 0-5 days (Tampere, Finland) or at 6 weeks (Cape Town, South Africa). Eye tracking was used to measure oculomotor orienting to peripheral visual stimuli and attention disengagement from central stimuli at 8 months (Tampere) or at 6 months (Cape Town) of age. In the Tampere cohort, a marginal positive correlation between fundamental frequency of cry (F0) and visual attention disengagement was observed; infants with a higher neonatal F0 were slower to shift gaze away from the central stimulus to the peripheral stimulus. However, a similar correlation was not observed in the Cape Town cohort. No associations between F0 and oculomotor orienting were observed in either cohort. We discuss possible factors influencing the discrepancy in results between the cohorts and suggest directions for future research investigating the potential of early cry analysis in predicting later cognitive development.

neuroscience↗