A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

The germline mutations of the CHEK2 gene are associated with an increased risk of polycythaemia vera

“…The median age of the cohort was 62 years. All molecular and statistical analyses were performed as previously described (Janiszewska et al , ). The gene mutations were investigated in DNA from peripheral blood (PB) and buccal swabs of patients, and in DNA from PB of 312 healthy persons, which formed the control group.…”

“…The molecular mechanisms underlying the development of myeloproliferative neoplasms (MPNs) are still not sufficiently well understood, although the association of MPNs pathogenesis with some gene alterations, especially somatic, have been reported (Tefferi, ; Bench et al , ). Recently, we demonstrated a strong association of germline mutations in the CHEK2 tumour suppressor gene with the increased risk of essential thrombocythaemia (ET) (Janiszewska et al , ). CHEK2 plays a key role in cell cycle regulation, coordination of DNA repair and apoptosis (Bartek & Lukas, ).…”

“…A CHEK2 mutation was found in 15 (14·1%) patients (Table ), 14 of whom were heterozygous and one was homozygous (p.I157T). The frequency of CHEK2 mutations was similar to that previously reported in ET patients (15·1%) (Janiszewska et al , ). All mutations were present both in DNA from PB and buccal swabs of patients, confirming their constitutional nature.…”

“…The risk of PV was three times higher in CHEK2 ‐positive patients, compared to both the control group [odds ratio (OR) = 3·0, P = 0·004] and general Polish population (OR = 2·7, P = 0·001) (Table ), and was similar to the previously reported risk of ET (Janiszewska et al , ). Thus, the estimated risk of PV and ET was found to be two times higher than the risk of breast cancer in women with CHEK2 mutations (Cybulski et al , ).…”

Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

“…Mutations in genes of this pathway compromise DNA repair and are linked to several types of malignancies and heritable cancer syndromes, [53][54][55][56] Although the germ line variants CHEK2 1100delC and ATM F858L have been associated with chronic lymphocytic leukemia, 57 sparse data exist for their relationship to myeloid malignancies, including MPN. 58,59 Somatic mutations in CHEK2 were recently identified in 3 of 151 MPN patients, 12 highlighting a potential role of this gene in MPN pathogenesis. The long intergenic noncoding RNA PINT is regulated by p53 and interacts with polycomb repressive complex 2, a key regulator of hematopoietic stem cell differentiation and maintenance frequently inactivated in myeloid malignancies.…”