Both germline and somatic deleterious mutations tend to be concentrated in the oligonucleotide/oligosaccharide-binding (OB) folds of POT1, regions which are critical to its binding to the single-stranded telomeric DNA and telomere maintenance.( Gu, et al 2016) Here, we demonstrate that two HL families have mutations in POT1 and demonstrate functional consequences of POT1 mutations in vitro and in vivo. POT1 germline mutations have been found in high-risk families with melanoma, colorectal cancer, glioma, Li-Fraumeni like syndrome, and chronic lymphocytic leukaemia. Notably, germline and somatic mutations have been reported in the key telomere biology gene, POT1 (protection of telomeres 1). Germline mutations in genes of the shelterin telomere protection complex have been identified in several familial cancers. Classical Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B cell origin with an age-adjusted incidence in the United States of 2.6/100,000.( Howlander, et al 2016) Aetiological clues about HL are suggested by 1) the bimodal age distribution, with one peak occurring in young adulthood and a second peak after age 50 years, 2) elevated risk in males, 3) elevated risk in individuals with higher socioeconomic status and from smaller families, 4) the occurrence of Epstein–Barr virus in HL tumour cells and 5) strong familial risk.( Caporaso, et al 2009) We previously analysed data from registries in Scandinavia and found significant familial aggregation of HL.( Goldin, et al 2004) The human leucocyte antigen (HLA) region on chromosome 6 has been associated with HL( McAulay and Jarrett 2015) and other loci have been identified through genome-wide association studies Identification of genes with major susceptibility effects has been more difficult although a few rare variants have been identified in single families.( Ristolainen, et al 2015, Saarinen, et al 2011, Salipante, et al 2009) We recently conducted whole exome sequencing (WES) in HL families and identified a mutation in KDR (kinase insert domain receptor) associated with disease in two families.( Rotunno, et al 2016)
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