Lynch Syndrome Genetics and Clinical Implications

Päivi Peltomäki, Minna Nyström, Jukka-Pekka Mecklin, Toni T Seppälä.

Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% of unselected patients with colorectal or endometrial cancer and 10%-15% of those with DNA mismatch repair-deficient tumors. Previous studies have established the genetic basis of LS predisposition, but there have been significant advances recently in the understanding of the molecular pathogenesis of LS tumors, which has important implications in clinical management. At the same time, immunotherapy has revolutionized the treatment of advanced cancers with DNA mismatch repair defects. We aim to review the recent progress in the LS field and discuss how the accumulating epidemiologic, clinical, and molecular information has contributed to a more accurate and complete picture of LS, resulting in genotype- and immunologic subtype-specific strategies for surveillance, cancer prevention, and treatment.

PMID: 36706841


Identification of DHX40 as a candidate susceptibility gene for colorectal and hematological neoplasia

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.

PMID: 37696923