	US 11,725,248 B2
	Evaluation of mantle cell lymphoma and methods related thereto
Louis M. Staudt, Bethesda, MD (US); David William Scott, Vancouver (CA); George W. Wright, Rockville, MD (US); Andreas Rosenwald, Wurzburg (DE); Pau Abrisqueta, Barcelona (ES); Rita Braziel, West Linn, OR (US); Elias Campo Guerri, Barcelona (ES); Wing C. Chan, Pasadena, CA (US); Joseph M. Connors, Vancouver (CA); Jan Delabie, Toronto (CA); Diego Villa, Vancouver (CA); Kai Fu, Omaha, NE (US); Randy D. Gascoyne, North Vancouver (CA); Timothy Greiner, Council Bluffs, IA (US); Elaine S. Jaffe, Great Falls, VA (US); Pedro Jares, Barcelona (ES); Anja Mottok, Vancouver (CA); German Ott, Bietigheim-Bissingen (DE); Lisa M. Rimsza, Scottsdale, AZ (US); Graham Slack, Richmond (CA); Dennis Weisenburger, Glendora, CA (US); Erlend B. Smeland, Oslo (NO); and James Robert Cook, Shaker Heights, OH (US)
Assigned to The United States of America, as represented by the Secretary, Department of Health and Human Services, Bethesda, MD (US); British Columbia Cancer Agency Branch, Vancouver (CA); Julius-Maximilians-University of Würzburg, Würzburg (DE); Oregon Health & Science University, Portland, OR (US); Hospital Clinic de Barcelona, Barcelona (ES); Universitat de Barcelona, Barcelona (ES); Oslo University Hospital HF, Oslo (NO); The Cleveland Clinic Foundation, Cleveland, OH (US); and Mayo Foundation for Medical Education and Research, Rochester, MN (US)
Appl. No. 16/94,965
Filed by The United States of America, as represented by the Secretary, Department of Health and Human Services, Bethesda, MD (US); British Columbia Cancer Agency Branch, Vancouver (CA); Julius-Maximilians—University of Würzburg, Würzburg (DE); Oregon Health & Science University, Portland, OR (US); Hospital Clinic de Barcelona, Barcelona (ES); Universitat de Barcelona, Barcelona (ES); Oslo University Hospital HF, Oslo (NO); Board of Regents of the University of Nebraska, Lincoln, NE (US); The Cleveland Clinic Foundation, Cleveland, OH (US); and Mayo Foundation for Medical Education and Research, Rochester, MN (US)
PCT Filed Apr. 20, 2017, PCT No. PCT/US2017/028628 § 371(c)(1), (2) Date Oct. 19, 2018, PCT Pub. No. WO2017/184861, PCT Pub. Date Oct. 26, 2017.
Claims priority of provisional application 62/325,213, filed on Apr. 20, 2016.
Prior Publication US 2019/0153539 A1, May 23, 2019
Int. Cl. C12Q 1/6886 (2018.01)

CPC C12Q 1/6886 (2013.01) [C12Q 2600/106 (2013.01); C12Q 2600/118 (2013.01); C12Q 2600/158 (2013.01)]

20 Claims

1. A method of determining a survival predictor score of a human subject having mantle cell lymphoma (MCL), which method comprises:

(a) providing a formalin-fixed and paraffin-embedded (FFPE) biopsy sample from the subject;

(b) isolating RNA gene expression product from the biopsy sample;

(c) obtaining gene expression data from the RNA gene expression product, wherein the gene expression data comprises signal values that represent expression levels for each gene of the table below:


	Anti-
	Pro-						Re-
	liferation/				Tar-	Cap-	por-
	House				get	ture	ter
	keeper/		Gen-		DNA	Probe	Probe
	Pro-		Bank		(SEQ	(SEQ	(SEQ
Human	liferation	Coeff.	Acces-	Posi-	ID	ID	ID
Gene	Gene	Value	sion	tion	NO:)	NO:)	NO:)

ATL1	Anti-	−19.64	NM_	1141-	1	56	111
	Pro-		015915.4	1240
	liferation
FMNL3	Anti-	−21.46	NM_	2434-	2	57	112
	Pro-		175736.4	2533
	liferation
GLIPR1	Anti-	−29.91	NM_	256-	3	58	113
	Pro-		006851.2	355
	liferation
ZDHHC21	Anti-	−23.47	NM_	713-	4	59	114
	Pro-		178566.4	812
	liferation
CHD4	House	0.75	NM_	2681-	5	60	115
	keeper		001273.2	2780
ERBB2IP	House	0.75	NM_	3676-	6	61	116
	keeper		018695.2	3775
GIT2	House	0.75	NM_	606-	7	62	117
	keeper		057169.2	705
GSK3B	House	0.75	NM_	926-	8	63	118
	keeper		002093.2	1025
HSPA9	House	0.75	NM_	976-	9	64	119
	keeper		004134.4	1075
IK	House	0.75	NM_	557-	10	65	120
	keeper		006083.3	656
MLL2	House	0.75	NM_	6071-	11	66	121
	keeper		003482.3	6170
NEU3	House	0.75	NM_	1841-	12	67	122
	keeper		006656.5	1940
R3HDM1	House	0.75	NM_	1276-	13	68	123
	keeper		015361.2	1375
RANBP9	House	0.75	NM_	2001-	14	69	124
	keeper		005493.2	2100
RC3H2	House	0.75	NM_	2911-	15	70	125
	keeper		018835.2	3010
TRIM56	House	0.75	NM_	2571-	16	71	126
	keeper		030961.1	2670
UBXN4	House	0.75	NM_	344-	17	72	127
	keeper		014607.3	443
VAC14	House	0.75	NM_	1476-	18	73	128
	keeper		018052.3	1575
VRK3	House	0.75	NM_	821-	19	74	129
	keeper		016440.3	920
WAC	House	0.75	NM_	756	20	75	130
	keeper		100486.2	-855
WDR55	House	0.75	NM_	816-	21	76	131
	keeper		017706.4	915
ZNF598	House	0.75	NM_	2369-	22	77	132
	keeper		178167.2	2468
CCNB2	Pro-	6.01	NM_	981-	23	78	133
	liferation		004701.2	1080
CDC20	Pro-	6.35	NM_	431-	24	79	134
	liferation		001255.2	530
CDKN3	Pro-	6.4	NM_	511-	25	80	135
	liferation		005192.3	610
E2F2	Pro-	6.02	NM_	3606-	26	81	136
	liferation		004091.2	3705
ESPL1	Pro-	6.5	NM_	1286-	27	82	137
	liferation		012291.4	1385
FAM83D	Pro-	5.92	NM_	866-	28	83	138
	liferation		030919.2	965
FOXM1	Pro-	6.55	NM_	3209-	29	84	139
	liferation		021953.2	3308
H2AFX	Pro-	6.08	NM_	1393-	30	85	140
	liferation		002105.2	1492
KIF2C	Pro-	6.19	NM_	1941-	31	86	141
	liferation		006845.3	2040
MKI67	Pro-	6.65	NM_	4021-	32	87	142
	liferation		002417.2	4120
NCAPG	Pro-	6.44	NM_	781-	33	88	143
	liferation		022346.3	880
TOP2A	Pro-	6.46	NM_	5377-	34	89	144
	liferation		001067.2	5476
ZWINT	Pro-	5.41	NM_	851-	35	90	145;
	liferation		007057.3	950

and

(d) determining a survival predictor score from the gene expression data, wherein the survival predictor score is determined by:

(1) log transforming each signal value of each gene obtained in (c) to obtain a log transformed value for each gene,

(2) multiplying the log transformed value of each gene obtained in (d)(1) by the corresponding

coefficient value for the respective gene listed in the table in (c) to obtain a multiplication product for each gene, and

(3) summing the multiplication products of each gene obtained in (d)(2).