血液病融合基因检测的质量保证
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MYB-GATA1 NPM1-ALK NPM1-TYK2 NUP98-KDM5A NUP98-NSD1 PICALM-MLLT10 RBM15-MKL1 RUNX1-RUNX1T1 STIL-TAL1 TCF3-HLF TCF3-PBX1 TPM3-ALK
%
ABL1 translocations
ABL2 translocations
2.AML1-ETO(1) 6.CBFB-MYH11(8) 10.FIP1L1-PDGFRA(5) 14.MLL-AF1q(4) 18.MLL-AFX(4) 22.NPM-ALK(1) 26.NUP98-HOXD13(1) 30.SET-CAN(1) 34.TEL-PDGFRB(1) 2. ERG del(2)
In 2009, the WHO developed accredited primary reference reagents for calibration of secondary reference reagents
In 2011, Secondary reference reagents calibrated to the primary make materials the IS more accessible
e
aFD X8 G
971
Biblioteka Baidu
Gen-ome
Ex-ome
Vari-ome
Muta-ome
36 FG 12191
022 4 FG
259
AML 016
Front. Med. DOI:10.1007/s11684-018-0616-1
3114
AML
36 36%
23B 12
h
3
Haematologica 2016 101: 541-58
m bb
b
i m
b
m
·
.Robustness
m
9. 2
9
87
.2
m
.22
2 52
9
7
9 NIWL I KTLIQ/ VS JL I VSOPLV LPPLT
a(
d
+
9
7
b
9
7
i m
b
s
F8 (
X
F8 ( -
F8 ( +
F8 ( +
ATIC-ALK BIRC3 MALT1 CBFA2T3-GLIS2 CBFB-MYH11 CLTC-ALK CTLA-CD28 DEK-NUP214 DUSP22-IRF4 ETV6-RUNX1 GATA2, MECOM ITK-SYK KAT6A-CREBBP MNX1-ETV6
Xrb
r
t
XX
X
·
.Robustness
9. 2
9
87
.2
.22
3B
m
8-16 primers multiples PCR
a
3SPST 3SKORM
%$ ! V2.6 Protocol of Fusion Genes Screening in Leukemia Using
Multiplex Nested PCR Method Version 2.6
23B 12
In 2003, IRIS trial established standardized baseline and MMR value
In 2005, the CML meeting in Bethesda proposed an international scale (IS), with the IRIS standardized baseline defined as 100% IS , and MMR defined as 0.1% IS
T=X" BCR-5Exon3,
d 2 y/ 29 y
&.%-) V2.6! +
0 Protocol of Fusion Genes Screening in Leukemia Using
Multiplex Nested PCR Method 6',MD-R-FGS-V2.6B
Blood. 2012; 120(4):737-47
g li
(+
21
.
21
.
NEJM 2015;373:1541-52.
Cancer 2015;121:3577-90
i
Estimated frequencies of BCP-ALL subtypes in children Blood. 2017;130(12):1395-1401
u V2.1 W 1. 2"d-g HOX11 %]1._NR 2. 6 V2.0 W _ H261 , H262 >dgdv,dvB+ F581 , F582 3. Z E2A-E =XI E2A-C&@2VO[24 758bp 4. B FIP1L1-PDGFRA m)1.NR=X2"NR FIP1L1ex9-PDGFRA m)1 .0 5. tDw=Xj(j(Hfi#
J Mol Diagn. 2013;15(5):565-76.
aABL1 is probably the best, but also BCR and GUS are acceptable
Leukemia (2003) 17, 2474–2486
Leukemia (2003) 17, 2318–2357
u V2.5 W 1. 'Sd-g _ HOX11 %]1.2" RPN1-EVI1 m)1. 2. /d g2" ZNF198-FGFR1 m)1._NR
u V2.6 W 1. d g ZNF198-FGFR1 m)1.NR9(F761F771F762F772uc kdg`:_=X9(B F661F671F662F672 2. /dg " BCR-FGFR1 m)1._NR
08
(
KMT2A-translocated MYC translocations NTRK3 translocations PDCD1LG2 translocations PDGFRA-rearrangement PDGFRB-rearrangement RARA-rearrangment TBL1XR1 translocations TYK2 translocations
Current Genomics, 2017, 18, 378-384
BCR e8
PRDM12 Exon4 112bp
ABL1 a2
PML-RARA
Z
( (( +
TEL-AML1
CBFB-MYH11
E2A-PBX1 TLS-ERG SIL-TAL1 DEK-CAN others
MLL AML1-ETO
u V2.2 W 1. 2" R882 =X PML-RARA L 0, V 0H5G$ 2. hML 2" BCR-ABL1 N_0—BCR-ABL1 e1a3 0
u V2.3 W 1. 2"rq&=X E2A-F , E2A-Gd 7 e&@2VO2" 847bp 2. Z *zl_Aa!o=X
23B 12
Approximately 100 laboratories received two blinded samples for BCR-ABL1 RT-qPCR analysis: a baseline sample containing undiluted K562 cell-line RNA and a post-treatment sample containing K562 RNA (dilution 1:10,000 in nonCML cell RNA). Each laboratory measured the BCR-ABL1 RNA ratio by its own validated method, and reported back to CAP the relative log reduction of the post- treatment sample compared with the baseline sample.
3.AML1-MDS1(2) 7.DEK-CAN(1) 11.MLL-AF10(18) 15.MLL-AF4(12) 19.MLL-ELL(8) 23.NPM-MLF1(1) 27.PLZF-RARA(2) 31.SIL-TAL1(1) 35.TLS-ERG(5)
4.BCR-ABL1(6) 8.E2A-HLF(3) 12.MLL-AF17(1) 16.MLL-AF6(4) 20.MLL-ENL(4) 24.NPM-RARA(2) 28.PML-RARA(5) 32.TEL-ABL1(2) 36.ZNF198-FGFR1(1)
B
i
(
A 3B
X X
s X
i m
b
E( +a
i
1.AML1-EAP(1) 5.BCR-FGFR1(1) 9.E2A-PBX1(2) 13.MLL-AF1p(4) 17.MLL-AF9(8) 21.MLL-PTD(5) 25.NUP98-HOXA9(1) 29.RPN1-EVI1(1) 33.TEL-AML1(2) 1. IKZF1 del(9)
,#
MD-R-FGS-V2.6A
')( * 2015-10-26
& "
1 +/ 29 +
WJHIsF
u V1.0 W Z3x7< PCR EPNR8p_ 29 b^n\`m)1., 2 b%]1.Q#
u V2.0 W 1. #=Xrq, PCR ?YK2"NRUC; 2. 'S V1.0 Wd-g HOX11 ,d g EVI b%]1._NR 3. /d-g 2" AML1-EAP m)1._NRd g 2" FIP1L1-PDGFRA m )1._NR 4. hML 2" BCR-ABL1 N_0 - BCR-ABL1 b3a3 0
WHO2016
PDGFRB
2017 1Atlas of Genetics and Cytogenetics in Oncology and Haematology5
KMT2A.MLL
197
WHO2016: B-ALL, BCR-ABL1-like
0
-
(
,)
:1;(X X31 BX352 1
;9DX6 D)XD5D(XD )
#132 4 2015-10-26
$/" *
( 1 5/ 15 5
m
n
3B
103 copies each 101 copies each
t
102 copies each
i
0 copy each
t
t
AML1-ETO PML-RARA V
d
A 3B
%
BCL6 translocations
CD274 translocations
CRLF2-rearrangements
CSF1R translocations
EPOR translocations
FGFR1-rearrangement
IGH-translocations
JAK2 translocations
/ 1KLPIOKL0 SRKSR0 IRK CLIVVPL0 A 3B
/ 23B
P<0.001 P=0.007
N Engl J Med 2003;349:1423-32.
Minimal Residual Disease in Chronic Myeloid Leukemia N Engl J Med 2003; 349:1399-1401
BCR-ABL1
.-
MLL-AF9
MLL-AF10
dupMLL
MLL-AF6
MLL-AF4
MLL-ELL MLL-ENL MLL-AF1q MLL-AF1p
Haematologica 2016 101: 541-558
Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 drivenchronic myeloid leukemia under first-line therapy with imatinib. Haematologica 2014 99: 1441-7
In 2006,the Adelaide laboratory (the Mannheim in Europe) initiated a process to develop and validate laboratory-specific conversion factors (CFs) to convert local values to IS values
MYB-GATA1 NPM1-ALK NPM1-TYK2 NUP98-KDM5A NUP98-NSD1 PICALM-MLLT10 RBM15-MKL1 RUNX1-RUNX1T1 STIL-TAL1 TCF3-HLF TCF3-PBX1 TPM3-ALK
%
ABL1 translocations
ABL2 translocations
2.AML1-ETO(1) 6.CBFB-MYH11(8) 10.FIP1L1-PDGFRA(5) 14.MLL-AF1q(4) 18.MLL-AFX(4) 22.NPM-ALK(1) 26.NUP98-HOXD13(1) 30.SET-CAN(1) 34.TEL-PDGFRB(1) 2. ERG del(2)
In 2009, the WHO developed accredited primary reference reagents for calibration of secondary reference reagents
In 2011, Secondary reference reagents calibrated to the primary make materials the IS more accessible
e
aFD X8 G
971
Biblioteka Baidu
Gen-ome
Ex-ome
Vari-ome
Muta-ome
36 FG 12191
022 4 FG
259
AML 016
Front. Med. DOI:10.1007/s11684-018-0616-1
3114
AML
36 36%
23B 12
h
3
Haematologica 2016 101: 541-58
m bb
b
i m
b
m
·
.Robustness
m
9. 2
9
87
.2
m
.22
2 52
9
7
9 NIWL I KTLIQ/ VS JL I VSOPLV LPPLT
a(
d
+
9
7
b
9
7
i m
b
s
F8 (
X
F8 ( -
F8 ( +
F8 ( +
ATIC-ALK BIRC3 MALT1 CBFA2T3-GLIS2 CBFB-MYH11 CLTC-ALK CTLA-CD28 DEK-NUP214 DUSP22-IRF4 ETV6-RUNX1 GATA2, MECOM ITK-SYK KAT6A-CREBBP MNX1-ETV6
Xrb
r
t
XX
X
·
.Robustness
9. 2
9
87
.2
.22
3B
m
8-16 primers multiples PCR
a
3SPST 3SKORM
%$ ! V2.6 Protocol of Fusion Genes Screening in Leukemia Using
Multiplex Nested PCR Method Version 2.6
23B 12
In 2003, IRIS trial established standardized baseline and MMR value
In 2005, the CML meeting in Bethesda proposed an international scale (IS), with the IRIS standardized baseline defined as 100% IS , and MMR defined as 0.1% IS
T=X" BCR-5Exon3,
d 2 y/ 29 y
&.%-) V2.6! +
0 Protocol of Fusion Genes Screening in Leukemia Using
Multiplex Nested PCR Method 6',MD-R-FGS-V2.6B
Blood. 2012; 120(4):737-47
g li
(+
21
.
21
.
NEJM 2015;373:1541-52.
Cancer 2015;121:3577-90
i
Estimated frequencies of BCP-ALL subtypes in children Blood. 2017;130(12):1395-1401
u V2.1 W 1. 2"d-g HOX11 %]1._NR 2. 6 V2.0 W _ H261 , H262 >dgdv,dvB+ F581 , F582 3. Z E2A-E =XI E2A-C&@2VO[24 758bp 4. B FIP1L1-PDGFRA m)1.NR=X2"NR FIP1L1ex9-PDGFRA m)1 .0 5. tDw=Xj(j(Hfi#
J Mol Diagn. 2013;15(5):565-76.
aABL1 is probably the best, but also BCR and GUS are acceptable
Leukemia (2003) 17, 2474–2486
Leukemia (2003) 17, 2318–2357
u V2.5 W 1. 'Sd-g _ HOX11 %]1.2" RPN1-EVI1 m)1. 2. /d g2" ZNF198-FGFR1 m)1._NR
u V2.6 W 1. d g ZNF198-FGFR1 m)1.NR9(F761F771F762F772uc kdg`:_=X9(B F661F671F662F672 2. /dg " BCR-FGFR1 m)1._NR
08
(
KMT2A-translocated MYC translocations NTRK3 translocations PDCD1LG2 translocations PDGFRA-rearrangement PDGFRB-rearrangement RARA-rearrangment TBL1XR1 translocations TYK2 translocations
Current Genomics, 2017, 18, 378-384
BCR e8
PRDM12 Exon4 112bp
ABL1 a2
PML-RARA
Z
( (( +
TEL-AML1
CBFB-MYH11
E2A-PBX1 TLS-ERG SIL-TAL1 DEK-CAN others
MLL AML1-ETO
u V2.2 W 1. 2" R882 =X PML-RARA L 0, V 0H5G$ 2. hML 2" BCR-ABL1 N_0—BCR-ABL1 e1a3 0
u V2.3 W 1. 2"rq&=X E2A-F , E2A-Gd 7 e&@2VO2" 847bp 2. Z *zl_Aa!o=X
23B 12
Approximately 100 laboratories received two blinded samples for BCR-ABL1 RT-qPCR analysis: a baseline sample containing undiluted K562 cell-line RNA and a post-treatment sample containing K562 RNA (dilution 1:10,000 in nonCML cell RNA). Each laboratory measured the BCR-ABL1 RNA ratio by its own validated method, and reported back to CAP the relative log reduction of the post- treatment sample compared with the baseline sample.
3.AML1-MDS1(2) 7.DEK-CAN(1) 11.MLL-AF10(18) 15.MLL-AF4(12) 19.MLL-ELL(8) 23.NPM-MLF1(1) 27.PLZF-RARA(2) 31.SIL-TAL1(1) 35.TLS-ERG(5)
4.BCR-ABL1(6) 8.E2A-HLF(3) 12.MLL-AF17(1) 16.MLL-AF6(4) 20.MLL-ENL(4) 24.NPM-RARA(2) 28.PML-RARA(5) 32.TEL-ABL1(2) 36.ZNF198-FGFR1(1)
B
i
(
A 3B
X X
s X
i m
b
E( +a
i
1.AML1-EAP(1) 5.BCR-FGFR1(1) 9.E2A-PBX1(2) 13.MLL-AF1p(4) 17.MLL-AF9(8) 21.MLL-PTD(5) 25.NUP98-HOXA9(1) 29.RPN1-EVI1(1) 33.TEL-AML1(2) 1. IKZF1 del(9)
,#
MD-R-FGS-V2.6A
')( * 2015-10-26
& "
1 +/ 29 +
WJHIsF
u V1.0 W Z3x7< PCR EPNR8p_ 29 b^n\`m)1., 2 b%]1.Q#
u V2.0 W 1. #=Xrq, PCR ?YK2"NRUC; 2. 'S V1.0 Wd-g HOX11 ,d g EVI b%]1._NR 3. /d-g 2" AML1-EAP m)1._NRd g 2" FIP1L1-PDGFRA m )1._NR 4. hML 2" BCR-ABL1 N_0 - BCR-ABL1 b3a3 0
WHO2016
PDGFRB
2017 1Atlas of Genetics and Cytogenetics in Oncology and Haematology5
KMT2A.MLL
197
WHO2016: B-ALL, BCR-ABL1-like
0
-
(
,)
:1;(X X31 BX352 1
;9DX6 D)XD5D(XD )
#132 4 2015-10-26
$/" *
( 1 5/ 15 5
m
n
3B
103 copies each 101 copies each
t
102 copies each
i
0 copy each
t
t
AML1-ETO PML-RARA V
d
A 3B
%
BCL6 translocations
CD274 translocations
CRLF2-rearrangements
CSF1R translocations
EPOR translocations
FGFR1-rearrangement
IGH-translocations
JAK2 translocations
/ 1KLPIOKL0 SRKSR0 IRK CLIVVPL0 A 3B
/ 23B
P<0.001 P=0.007
N Engl J Med 2003;349:1423-32.
Minimal Residual Disease in Chronic Myeloid Leukemia N Engl J Med 2003; 349:1399-1401
BCR-ABL1
.-
MLL-AF9
MLL-AF10
dupMLL
MLL-AF6
MLL-AF4
MLL-ELL MLL-ENL MLL-AF1q MLL-AF1p
Haematologica 2016 101: 541-558
Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 drivenchronic myeloid leukemia under first-line therapy with imatinib. Haematologica 2014 99: 1441-7
In 2006,the Adelaide laboratory (the Mannheim in Europe) initiated a process to develop and validate laboratory-specific conversion factors (CFs) to convert local values to IS values