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意义不明的克隆性细胞减少症

Clonal cytopenia of undetermined significance ,CCUS

夏成青

更新时间:2022-10-16 21:11:18

概述:

指在克隆性造血的背景上出现持续的不能用血液或非血液疾病解释的一系或多系血细胞减少。2023年第五版WHO淋巴造血肿瘤分类将其作为髓系肿瘤前驱病变中的一个独立的实体。

诊断要点:

1. 骨髓或外周血可检出髓系驱动基因突变,突变丰度 (VAF)≥2%(男性X连锁基因突变是VAF≥4%)。
2. 骨髓细胞学检查可能存在细胞异型,但不满足骨髓增生异常肿瘤(MDS)的诊断标准。
3. 骨髓活检排除其它血细胞减少的原因,如其它髓系肿瘤。

4. 不符合其它髓系肿瘤的诊断标准。


其诊断标准是:满足下列所有标准可诊断为意义不明的克隆性细胞减少症,如仅满足下列条件中的2和3条,可诊断为意义不明的特发性细胞减少(ICUS)
1. 骨髓或外周血可检出髓系肿瘤相关驱动基因突变,突变丰度 (VAF)≥2%(男性X连锁基因突变是VAF≥4%) ;或者髓系细胞克隆性染色体异常。
2. 患者有持续4个月以上的无明确原因的一系或多系细胞减少持续性细胞减少病史。
3. 骨髓检查不能满足髓系肿瘤诊断标。




分子标记:

髓系肿瘤相关的分子变异如下表

Gene Name

Criteria for Classification as a Clonal Haematopoiesis Driver Mutation

Reference Transcript


DNMT3A

Frameshift/nonsense/splice-site; Missense in aa range: p.292-350, p.482-614 and p.634-912

NM_022552

TET2

Frameshift/nonsense/splice-site; Missense in aa range: p.1104-1481 and p.1843-2002

NM_001127208

ASXL1

Frameshift/nonsense/splice-site in exon 11-12

NM_015338

JAK2

p.V617F; Missense/indel in aa range: p.536-547

NM_004972

TP53

Frameshift/nonsense/splice-site; Missense in aa range: p.72, p.95-288 and p.337

NM_001126112

SF3B1

Missense in terminal HEAT domains (p.529-1201)

NM_012433

PPM1D

Frameshift/nonsense/splice-site in exon 5/6

NM_003620

SRSF2

Missense/in-frame deletion involving P95

NM_003016

IDH1

Missense at p.R132

NM_005896

IDH2

Missense at p.R140 or p.R172

NM_002168

U2AF1

Missense at p.S34 / p.R156 / p.Q157

NM_006758

KRAS

Missense at  p.G12 / p.G13 / p.Q61 / p.A146

NM_033360

NRAS

Missense at p.G12 / p.G13 / p.Q61

NM_002524

CTCF

Frameshift/nonsense/splice-site, p.R377C, p.R377H, p.P378A, p.P378L

NM_006565

CBL

Missense in Linker/RING finger domains (p.345-434)

NM_005188

GNB1

Missense at p.K57 / p.G53 / p.I81

NM_002074

BRCC3

Frameshift/nonsense/splice-site

NM_024332

PTPN11

Missense in aa range p.58-76 and p.491-510

NM_002834

GNAS

Missense at p.R201

NM_016592

BCOR

Frameshift/nonsense/splice-site

NM_001123385

BCORL1

Frameshift/nonsense/splice-site

NM_021946

Other

 

BRAF

Missense in aa range p.590-615; Missense at p.G469

NM_004333

CALR

Frameshift in exon 9

NM_004343

CEBPA

Frameshift/nonsense/splice-site

NM_004364

CREBBP

Frameshift/nonsense/splice-site

NM_004380

CSF1R

Missense at p.L301 / p.Y969

NM_005211

CSF3R

T615A, T618I, truncating c.741-791

NM_000760

CUX1

Frameshift/nonsense/splice-site

NM_181552

ETV6

Frameshift/nonsense/splice-site

NM_001987

EZH2

Frameshift/nonsense/splice-site; Missense in SET domain (p.617-732)

NM_001203247

GATA2

Frameshift/nonsense/splice-site, p.R293Q, p.N317H, p.A318T, p.A318V, p.A318G, p.G320D, p.L321P, p.L321F, p.L321V, p.Q328P, p.R330Q, p.R361L, p.L359V, p.A372T, p.R384G, p.R384K

NM_001145661

JAK3

p.M511T, p.M511I, p.A572V, p.A572T, p.A573V, p.R657Q, p.V715I, p.V715A

NM_000215

KDM6A

Frameshift/nonsense/splice-site

NM_021140

KIT

ins503, p.V559A, p.V559D, p.V559G, p.V559I, p.V560D, p.V560A, p.V560G, p.V560E, del560, p.E561K, del579, p.P627L, p.P627T, p.R634W, p.K642E,  p.K642Q,  p.V654A,  p.V654E,  p.H697Y,  p.H697D,  p.E761D,  p.K807R,  p.D816H,  p.D816Y,  p.D816F,  p.D816I,  p.D816V,  p.D816H,  del551-559

NM_000222

KMT2A

Frameshift/nonsense/splice-site

NM_005933

MPL

p.S505G, p.S505N, p.S505C, p.L510P, del513, p.W515A, p.W515R, p.W515K, p.W515S, p.W515L, p.A519T, p.A519V, p.Y591D, p.W515-518KT

NM_005373

MYD88

p.L265P

NM_002468

NOTCH1

Frameshift/nonsense/splice-site/missense in exon 26-34

NM_017617

PHF6

Frameshift/nonsense/splice-site

NM_001015877

PIGA

Frameshift/nonsense/splice-site

NM_002641

PRPF40B

Frameshift/nonsense/splice-site

NM_001031698

PTEN

Frameshift/nonsense/splice-site

NM_000314

RAD21

Frameshift/nonsense/splice-site

NM_006265

RUNX1

Frameshift/nonsense/splice-site, p.S73F, p.H78Q, p.H78L, p.R80C, p.R80P, p.R80H, p.L85Q, p.P86L, p.P86H, p.S114L, p.D133Y, p.L134P, p.R135G, p.R135K,  p.R135S,  p.R139Q,  p.R142S,  p.A165V,  p.R174Q,  p.R177L,  p.R177Q,  p.A224T,  p.D171G,  p.D171V,  p.D171N,  p.R205W,  p.R223C

NM_001001890

SETBP1

p.D868N, p.D868T, p.S869N, p.G870S, p.I871T, p.D880N, p.D880Q

NM_015559

SF1

Frameshift/nonsense/splice-site

NM_004630

SF3A1

Frameshift/nonsense/splice-site

NM_005877

SMC1A

Missense at R96 / R586

NM_006306

SMC3

Frameshift/nonsense/splice-site

NM_005445

STAG2

Frameshift/nonsense/splice-site

NM_006603

STAT3

Missense in SH2 domain (p.580-670)

NM_139276

U2AF2

Missense in RNA recognition motifs domains (p.149-231, p.259-337, p.381-462)

NM_007279

WT1

Frameshift/nonsense/splice-site

NM_024426

ZRSR2

Frameshift/nonsense/splice-site

NM_005089

预后:

异常细胞克隆越大,体细胞突变数量越多,存在TP53、PPM1D、JAK2、RUNX1、SF3B1、SRSF2、U2AF1、IDH2和IDH1等基因突变进展为髓系肿瘤的风险越高,另外,血细胞减少的程度,特别是有细胞毒药物暴露史的进展为血液肿瘤的风险也增加;单一的DNMT3A突变患者进展为MDS或急性髓系白血病的风险较低。

参考文献:

2023第五版WHO淋巴造血肿瘤分类
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