Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.
Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms.
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从意义不明的单克隆性伽马病(MGUS)和阴燃骨髓瘤(SMM)到恶性多发性骨髓瘤(MM)和浆细胞白血病(PCL)的进展机制尚不清楚，但被认为涉及到遗传HITS的顺序获得。我们对MGUS(n=4)、高危(HR)-SMM(n=4)、MM(n=26)和PCL(n=2)进行了外显子组和全基因组测序，其中包括4例从HR-SMM转化为MM的病例，以确定推动疾病进展的遗传因素。非同义突变的模式和数量表明，MGUS病期的遗传复杂性低于MM，HR-SMM类似于MM，在所有阶段都存在克隆内异质性，并以转化为MM的HR-SMM为例，我们表明克隆内异质性是该病的典型特征。在疾病的HR-SMM阶段，引起多发性骨髓瘤所需的大多数基因变化已经存在。这些数据表明，克隆进展是HR-SMM向MM转化的关键特征，因此，典型的侵袭性临床优势克隆已存在于SMM阶段，并可在该阶段进行治疗干预。
The mechanisms involved in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole genome sequencing on a series of MGUS (n=4), high risk (HR)-SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors which drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
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影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
20.3
作者：
Davies, FE;Dring, AM;Anderson, KC
通讯作者：
Anderson, KC
影响因子：
7
作者：
Lunter, Gerton;Goodson, Martin
通讯作者：
Goodson, Martin
影响因子：
64.5
作者：
Nik-Zainal S;Van Loo P;Wedge DC;Alexandrov LB;Greenman CD;Lau KW;Raine K;Jones D;Marshall J;Ramakrishna M;Shlien A;Cooke SL;Hinton J;Menzies A;Stebbings LA;Leroy C;Jia M;Rance R;Mudie LJ;Gamble SJ;Stephens PJ;McLaren S;Tarpey PS;Papaemmanuil E;Davies HR;Varela I;McBride DJ;Bignell GR;Leung K;Butler AP;Teague JW;Martin S;Jönsson G;Mariani O;Boyault S;Miron P;Fatima A;Langerød A;Aparicio SA;Tutt A;Sieuwerts AM;Borg Å;Thomas G;Salomon AV;Richardson AL;Børresen-Dale AL;Futreal PA;Stratton MR;Campbell PJ;Breast Cancer Working Group of the International Cancer Genome Consortium
通讯作者：
Breast Cancer Working Group of the International Cancer Genome Consortium
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA