Research Group: Mosaicism for autosomal post-zygotic mutation

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Research Group: Mosaicism for autosomal post-zygotic mutation

The group’s primary scientific focus in on the identification of autosomal post-zygotic somatic mosaicism (PZMs), including both simple nucleotide variants (SNVs) and structural genomic rearrangements. We explore the transcriptomic and epigenetic effects of PZMs, with an emphasis on their involvement in the etiology of cancers, mostly breast cancer, as well as hereditary rare cancer genetic syndromes, such neurofibromatoses and schwannomatosis.

Recently, our group has identified the presence of subclonal somatic pathogenic variants in cancer-associated genes in biopsies of non-cancerous mammary glandular tissue, located distant from the primary tumor site. These variants exhibited significant allelic frequencies, indicating clonal expansion. Further investigation using ultra-sensitive duplex sequencing revealed multiple low-level subclonal hotspot pathogenic variants in frequently damaged genes, such as PIK3CA and TP53. The presence of pathogenic genetic alterations in seemingly normal mammary gland tissue that remains after breast-conserving surgery could pose a risk of recurrence and impact future treatment.

Our group specializes also in the field of neurofibromatoses (Prof. A. Piotrowski & Dr M. Koczkowska), which are rare genetic disorders, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN). These disorders predispose to a higher risk of developing specific malignancies compared to the general population, significantly increasing mortality. Due to the highly variable inter- and intrafamilial clinical presentation, wide allelic heterogeneity, and low-level mosaicism that can affect up to 40% of individuals with NF2, neurofibromatoses present a diagnostic challenge. A thorough assessment and comprehensive workup by an interdisciplinary team, including clinicians and molecular geneticists, is crucial to provide these individuals with a definite diagnosis, allowing for personalized surveillance and effective management at early stages of disease. We are currently working on the optimization and validation of high-throughput new generation sequencing technology available for detecting both constitutional and somatic mosaic pathogenic variants at very low level, down to 1-3% variant allele fraction.

Projects in progress:

  • Specific transcriptomic signature of mammary glandular tissue and tumors from patients with unfavorable long-term follow-up and post-zygotic mosaic pathogenic variants in a a cohort of breast cancer patients with poor long-term prognosis
  • Somatic pathogenic variants in stromal fibroblasts from breast cancer patients that may affect mammary glandular tissue via paracrine signaling
  • The role of rare driver mutations in the genesis of mammary tumors
  • Enhancing molecular diagnostics of the neurofibromatoses and related disorders