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Blood. 2016 Nov 10;128(19):2319-2326. doi: 10.1182/blood-2016-01-695692. Epub 2016 Aug 15.

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

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Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
Department of Haemato-Oncology, The Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom.
Department of Haematology, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom; and.
Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.


Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.

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