Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility
Menée à partir d'échantillons sanguins prélevés sur une patiente présentant plusieurs tumeurs, cette étude met en évidence un mécanisme par lequel des mutations constitutionnelles bi-alléliques de MAD1L1, un gène codant pour une protéine de contrôle de l'assemblage du fuseau mitotique, induisent une nouvelle variante du syndrome d'aneuploïdie panachée en mosaïque qui confère une forte suceptibilité tumorale
Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non–cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility. MAD1L1 mutations found in an individual with high tumor susceptibility and a systemic inflammation response to aneuploidy.
Science Advances 2022