期刊
BLOOD
卷 128, 期 19, 页码 2319-2326出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-01-695692
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资金
- Bloodwise [LRF05001, LRF06002, LRF13044]
- Cancer Research UK (Bobby Moore Fund) [C1298/A8362]
- Arbib Fund
- Leicester Experimental Cancer Medicine Centre [C325/A15575]
- ICR
- Sir John Fisher Foundation
- MRC [MC_U132670597, MR/N01104X/1, G1001799] Funding Source: UKRI
- Medical Research Council [MC_U132670597, G1001799, MR/N01104X/1] Funding Source: researchfish
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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