The CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis

In response to DNA damage, the cell cycle checkpoint kinase 2 (CHEK2) may phosphorylate p53, Cdc25A and Cdc25C, and regulate BRCA1 function, leading to cell cycle arrest and DNA repair. The truncating germline mutation CHEK2*1100delC abrogates kinase activity and confers low-penetrance susceptibility to breast cancer. We found CHEK2*1100delC in 0.5% of 190 oesophageal squamous cell carcinomas and in 1.5% of 196 oesophageal adenocarcinomas. In addition, we observed the mutation in 3.0% of 99 Barrett's metaplasias and 1.5% of 66 dysplastic Barrett's epithelia, both known precursor lesions of oesophageal adenocarcinoma. Since CHEK2*1100delC mutation frequencies did not significantly differ among oesophageal squamous cell carcinomas, adenocarcinomas and (dysplastic) Barrett's epithelia, as compared to healthy individuals, we conclude that the CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL