Alisa Olkinuora, Taina T Nieminen, Suvi Douglas, Anni Kauppinen, Mika Kontro, Juho Väänänen, Matti Kankainen, Ari Ristimäki, Markus Mäkinen, Päivi Lahermo, Caroline Heckman, Janna Saarela, Milla Salonen, Anna Lepistö, Heikki Järvinen, Jukka-Pekka Mecklin, Outi Kilpivaara, Ulla Wartiovaara-Kautto, Kimmo Porkka, Päivi Peltomäki.
Causative genes are mostly unknown for FCCTX, the mismatch repair-proficient category of familial colorectal cancers. Recent evidence suggests shared susceptibility factors between colorectal and hematological malignancies. We investigated 28 FCCTX families by exome sequencing, supplemented with genome sequencing, RNA-sequencing, and tumor studies to identify the predisposing genes. Guided by the findings, the exomes of ~400 patients with acute leukemia, myelodysplastic syndrome, and myeloma were examined. A family with hematological malignancies and cancers of the intestine and breast revealed a truncating variant in the DEAH-box RNA helicase gene DHX40 co-segregating with disease in seven family members. Neoplastic tissues revealed no apparent “second hit”, implying a haploinsufficiency model of tumorigenesis. DHX40 siRNA-treated cell lines exhibited a 13% increase in aberrantly spliced transcripts vs. GAPDH-siRNA or non-target siRNA-treated cells. In the hospital-based hematological series, 18% of germline and 28% of somatic exomes revealed possibly pathogenic DEAD/H box gene variants, including somatic variants of DHX40 in four. This study emphasizes aberrant RNA metabolism behind FCCTX and hematological neoplasia. Our observations on DHX40 suggest analogy to DDX41, a DEAD-box RNA helicase gene previously linked to myeloid malignancies.