The exceptional case of a person who has survived twelve tumours opens up new avenues for early diagnosis and immunotherapy in cancer by Dra. Carolina Villarroya, postdoctoral researcher at Malumbres Lab.

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 demon- strated 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 NF-kappa-B signaling both in aneuploid and euploid cells, suggesting a non–cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of delta-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.
This work has been published in Science Advances:

Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility