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Prediction of acute myeloid leukaemia risk in healthy individuals

机译：健康个体急性髓细胞白血病风险的预测

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摘要

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure(1). The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion(2,3). However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)(4-8). Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.
机译：急性髓细胞性白血病（AML）的发病率随年龄增长而增加，在65岁以后被诊断出死亡率超过90％。大多数病例无任何可察觉的早期症状出现，并且患者通常出现急性骨髓衰竭并发症（1）。这种从头开始的AML病例通常在经历克隆扩增的白血病前造血干细胞和祖细胞（HSPC）中积累体细胞突变（2,3）。但是，在不发展AML的健康个体衰老过程中，HSPC中也会反复出现AML突变，这种现象称为与年龄相关的克隆性造血（ARCH）（4-8）。在这里，我们使用深度测序来分析在AML中反复突变的基因，以区分罹患AML的高风险个体和具有良性ARCH的个体。我们分析了AML诊断前平均6.3年（AML前组）获得的95名个体的外周血细胞，以及414名未选择的年龄和性别匹配的个体（对照组）。 AML前病例与对照组不同，每个样本具有更多的突变，等位基因频率更高，表明克隆扩增更大，并且在特定基因中显示出丰富的突变。遗传参数用于推导可准确预测无AML生存率的模型；该模型在29个AML前病例和262个对照的独立队列中得到了验证。由于AML很少见，因此我们还使用大型电子健康记录数据库开发了AML预测模型，该数据库可识别风险较高的个体。总的来说，我们的发现提供了概念证明，即可以在恶性转化之前很多年将ARCH与AML前区分开。将来，这可以使早期检测和监视成为可能，并且可以帮助告知干预措施。

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  • 来源
    《Nature》 |2018年第7714期|400-404|共5页
  • 作者

    Abelson Sagi; Collord Grace; Ng Stanley W. K.; Weissbrod Omer; Cohen Netta Mendelson; Niemeyer Elisabeth; Barda Noam; Zuzarte Philip C.; Heisler Lawrence; Sundaravadanam Yogi; Luben Robert; Hayat Shabina; Wang Ting Ting; Zhao Zhen; Cirlan Julia; Pugh Trevor J.; Soave David; Ng Karen; Latimer Calli; Hardy Claire; Raine Keiran; Jones David; Hoult Diana; Britten Abigail; McPherson John D.; Johansson Mattias; Mbabaali Faridah; Eagles Jenna; Millers Jessica K.; Pasternack Danielle; Timms Lee; Krzyzanowski Paul; Awadalla Philip; Costa Rui; Segal Eran; Bratman Scott V; Beer Philip; Behjati Sam; Martincorena Inigo; Wang Jean C. Y.; Bowles Kristian M.; Ramon Quiros J.; Karakatsani Anna; La Vecchia Carlo; Trichopoulou Antonia; Salamanca-Fernandez Elena; Huerta Jose M.; Barricarte Aurelio; Travis Ruth C.; Tumino Rosario; Masala Giovanna; Boeing Heiner; Panico Salvatore; Kaaks Rudolf; Kraemer Alwin; Sieri Sabina; Riboli Elio; Vineis Paolo; Foll Matthieu; McKay James; Polidoro Silvia; Sala Nuria; Khaw Kay-Tee; Vermeulen Roel; Campbell Peter J.; Papaemmanuil Elli; Minden Mark D.; Tanay Amos; Balicer Ran D.; Wareham Nicholas J.; Gerstung Moritz; Dick John E.; Brennan Paul; Vassiliou George S.; Shlush Liran I;

  • 作者单位

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON, Canada;

    Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel;

    Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel;

    Weizmann Inst Sci, Dept Immunol, Rehovot, Israel;

    Clalit Res Inst, Tel Aviv, Israel;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Sch Clin Med, Cambridge, England;

    Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Sch Clin Med, Cambridge, England;

    Univ Toronto, Dept Med Biophys, Toronto, ON, Canada;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England;

    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    WHO, Int Agcy Res Canc, Lyon, France;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    Ontario Inst Canc Res, Toronto, ON, Canada;

    EBI, EMBL, Wellcome Genome Campus, Hinxton, England;

    Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    Univ East Anglia, Norwich Med Sch, Dept Mol Haematol, Norwich, Norfolk, England;

    Publ Hlth Directorate, Asturias, Spain;

    Hellenic Hlth Fdn, Athens, Greece;

    Hellenic Hlth Fdn, Athens, Greece;

    Hellenic Hlth Fdn, Athens, Greece;

    Univ Granada, Inst Invest Biosanitaria ibs GRANADA, Escuela Andaluza Salud Publ, Hosp Univ Granada, Granada, Spain;

    CIBERESP, CIBER Epidemiol & Publ Hlth, Madrid, Spain;

    CIBERESP, CIBER Epidemiol & Publ Hlth, Madrid, Spain;

    Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England;

    Civ MP Arezzo Hosp, Canc Registry & Histopathol Dept, Azienda Sanit Prov, Ragusa, Italy;

    ISPO, Canc Risk Factors & Life Style Epidemiol Unit, Canc Res & Prevent Inst, Florence, Italy;

    German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Potsdam, Germany;

    Univ Naples Federico II, Dipartimento Med Clin E Chirurg, Naples, Italy;

    German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany;

    Heidelberg Univ, Clin Cooperat Unit Mol Hematol Oncol, German Canc Res Ctr DKFZ, Heidelberg, Germany;

    Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy;

    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;

    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;

    WHO, Int Agcy Res Canc, Lyon, France;

    WHO, Int Agcy Res Canc, Lyon, France;

    Italian Inst Genom Med, Turin, Italy;

    ICO IDIBELL, Unit Nutr & Canc, Catalan Inst Oncol, Canc Epidemiol Res Program, Barcelona, Spain;

    Univ Cambridge, Cambridge, England;

    Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol & Vet Publ Hlth, Utrecht, Netherlands;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel;

    Clalit Res Inst, Tel Aviv, Israel;

    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

    WHO, Int Agcy Res Canc, Lyon, France;

    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England;

    UHN, Princess Margaret Canc Ctr, Toronto, ON, Canada;

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