Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

[Agenesis of inferior vena cava combined with multiple genetic predisposition in the case of deep venous thrombosis in a young male]. / Congenitális vena cava inferior malformatio és thrombosisra hajlamosító genetikai tényezók kombinált megjelenése fiatal férfi mélyvénás thrombosisában.

Deep venous thrombosis in the young age may be a complication of the rare congenital abnormality of the vena cava inferior. Genetic factors predisposing to thrombophilia in coincidence with vena cava malformation put the patients at much higher risk to develop thrombosis. The authors report a case of a 25-year old male who suffered from a massive deep venous thrombosis derived from the vena poplitea involving the vena iliaca communis. The molecular genetic examination of the patient revealed his combined genetic predisposition to venous thrombosis (Heterozygosity for Factor V. Leiden, Heterozygosity for prothrombin G20210A). Authors conclude that it is essential to perform all the relevant molecular genetic examinations to identify the presence of thrombophilic vulnerabilty and radiological imaging procedures in all cases of young patients with deep venous thrombosis if the suspicion of vascular malformation arises. The review of the literature revealed that the vena cava malformation in association with genetic factor predisposing to thrombophilia is an infrequent condition. In the authors knowledge this is the first report presenting a multiple combined genetic predisposition of risk factors in deep venous thrombosis.