來自英國(guó)紐卡斯?fàn)柎髮W(xué)的研究人員發(fā)現(xiàn)三種關(guān)鍵性的遺傳錯(cuò)誤：它們能夠決定成年病人如何患上白血病和對(duì)治療方法作出反應(yīng)，可能有助于醫(yī)生們改進(jìn)未來的治療方法,。2012年7月30日,，這項(xiàng)突破性研究發(fā)表在Journal of Clinical Oncology期刊上。
急性淋巴細(xì)胞白血病(acute lymphoblastic leukaemia, ALL)是一種血癌,，特征在于白細(xì)胞發(fā)生基因突變而不受控制地增殖而將健康的血細(xì)胞擠出去,。在這項(xiàng)研究中,，研究人員研究了450名被診斷患有ALL的青年人和成年人體內(nèi)白血病細(xì)胞中9個(gè)新發(fā)現(xiàn)的遺傳突變,。
他們證實(shí)這些新突變的發(fā)生率比期望中更高,，而且還發(fā)現(xiàn)三分之二以上的病人攜帶至少一個(gè)突變,。再者,，他們還發(fā)現(xiàn)這些新突變中的三個(gè)是“高風(fēng)險(xiǎn)”的標(biāo)記物,，攜帶這三種突變中之一的病人當(dāng)接受標(biāo)準(zhǔn)療法時(shí)有更加高的風(fēng)險(xiǎn)發(fā)生白血病復(fù)發(fā)或死亡,。超過四分之一的病人攜帶這些高風(fēng)險(xiǎn)突變中的一個(gè)或多個(gè)，這種突變發(fā)生率明顯高于ALL兒童中觀察到的相應(yīng)突變發(fā)生率,。
論文第一作者Anthony Moorman教授說,，“這項(xiàng)研究代表著我們?cè)诶斫獬赡耆薃LL遺傳突變的臨床重要性上取得一次重要性的進(jìn)展,。”(生物谷：Bioon.com)
本文編譯自Scientists identify genetic drivers of leukaemia
doi: 10.1200/JCO.2011.40.3907
PMC:
PMID:
IGH@ Translocations, CRLF2 Deregulation, and Microdeletions in Adolescents and Adults With Acute Lymphoblastic Leukemia
Anthony V. Moorman⇓, Claire Schwab, Hannah M. Ensor, Lisa J. Russell, Heather Morrison, Lisa Jones, Dino Masic, Bella Patel, Jacob M. Rowe, Martin Tallman, Anthony H. Goldstone, Adele K. Fielding and Christine J. Harrison
Purpose To determine the prevalence and prognostic impact of significant acute lymphoblastic leukemia (ALL) –related genes: CRLF2 deregulation (CRLF2-d), IGH@ translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, and EBF1 in adolescents and adults. Patients and Methods The cohort comprised 454 patients (age 15 to 60 years old) treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used to detect these genetic alterations. Results Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n = 13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There was little overlap between IGH@-t, CRLF2-d, and established chromosomal abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5-year event-free survival, relapse-free survival (RFS), and overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%, respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated with an inferior outcome in univariate but not multivariate analysis. In particular, CRLF2-d patients had a lower RFS compared with other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%, respectively). Conclusion CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.
