Driver mutations in ERBB2 are expanding in the male germline

Description

The epidermal growth factor family of receptor tyrosine kinases (ErbBs) is an important oncogene that plays a crucial role in regulating cell proliferation, survival, and differentiation during embryonic development, as well as in adult somatic tissue. Given the continuous replicative nature of the male germline, Erbb2 driver mutations could increase in frequency with age in the testes posing a higher risk of transmission of new mutations with severe early or late onset effects in the offspring. To explore this, we adapted duplex sequencing, an ultra-deep and highly accurate sequencing method to screen driver mutations in ERBB2 in sperm or testis DNA. We identified mutations that are found at increased frequencies in some sperm donors. Two of these mutations occur also in a large number of different donors suggesting that these novel variants are important driver mutations in the male germline. Further, we characterized the clonal expansion of candidate mutations in two post mortem testes from 70- and 73-year old donors by droplet digital PCR (ddPCR), along with the analysis of the functional changes in the downstream activation of the ERBB2 signaling pathway by biophysical methods. This unexpected enrichment of functionally activating mutations in sperm and testis might have unknown consequences in the offspring of these donors.

Period	22 Sept 2022
Event title	Österreichische Gesselschaft für Molkeluar Biologie und Technologie
Event type	Conference
Location	AustriaShow on map