Recurrent amplification of MYC and TNFRSF11B in 8q24 is associated
with poor survival in patients with gastric cancer
Supplementary results:
Independent cohort validation of MYC and TNFRSF11B at 8q24
An independent validation cohort of 413 cases was used to validate the association
between gains of MYC, TNFRSF11B, ESRP1, MMP9, and CSE1L and patient prognosis.
The general conditions of the patients in the training and validation cohorts are
comparable. Patients with a gain of either MYC or TNFRSF11B presented a shorter
median overall survival than those without gain (MYC: median survival: 23.24 months
vs. 42.77 months, P = 0.034; TNFRSF11B: median survival: 26.36 months vs. 30.06
months, P = 0.047, Supplementary Figures A and 1B), whereas there was no significant
difference in survival between the patients with a gain of MMP9, CSE1L, or ESRP1 and
those without gain (data not shown).
Moreover, the GC patients with a high copy number gain (copy number > 4) of MYC
or TNFRSF11B exhibited an even poorer overall survival than those with a copy number
gain (2 < copy number ≤ 4) and those with no gain (MYC: median survival: 12.26
months vs. 26.56 months vs. 42.77 months, P < 0.001; TNFRSF11B: median survival:
17.98 months vs. 26.66 months vs. 36.06 months, P = 0.015, Supplementary Figures C
and D).
Association of 8q24 gain with survival and clinicopathological features
The survival-related genes MYC and TNFRSF11B are found within a wide range of
amplified regions in 8q24, which spans approximately 20 million base pairs. We found
that the patient group with gains of both MYC and TNFRSF11B was markedly
segregated from non-gain group. The co-gain group presented a significantly lower
five-year survival rate than the non-gain group (median survival: 23.24 months vs.
45.14 months, P = 0.019, Supplementary Figure E). The statistical analysis showed that
the co-gain of MYC and TNFRSF11B was strongly associated with the depth of wall
invasion and TNM stage in both the training and validation cohorts (supplementary
Table 4).
Table 1S. Probe information.
Chromosome
chr20
chr8
chr8
chr20
chr8
chr8
chr20
Symbol
CSE1L
TNFRSF11B
ESRP1
MMP9
MYC
CCNE2
SRC
DNA srand
+
+
+
+
+
Probe set region
108-672
656-1260
8160-8805
1171-1782
674-1182
13207-13777
27895-28533
Chromosome region
47096244-47146892
120004976-120033563
95722575-95788869
44070953-44078606
128817497-128822855
95961627-95976659
35406501-35467234
Table 2S. Representative amplified genomic loci and genes by aCGH analysis.
Chromosome Region Location
chr20
p13
0-5M
p12.3
p12.2
p12.1
5-6M
10-11M
16-17M
p11.21-23 20-25M
chr8
chr7
chr13
Representative Genes
TCF15, PSMF1, SNRPB, TMC2, NOP56, EBF4, PTPRA, GNRH2,
MRPS26, OXT, AVP, UBOX5, FASTKD5, GFRA4, ADAM33, CENPB,
CDC25B, ANK2, SMOX, ADRA1D, PRND, PRNT, RASSF2, SLC23A2,
PCNA, CDS2
PROKR2, CHGB, TRMT6, MCM8, CRLS1, LRRN4, FERMT1
JAG1, BTBD3
SNRPB2, OTOR, BFSP1, DSTN, RRBP1, BANF2, SNX5, SNORD17,
OVOL2
CD93, NXT1, GZF1, NAPB, CST11, CST8, CST2, CST5, CST7, ACSS1,
VSX1, ENTPD6, PYGB, NLP
BCL2L1, PLAGL2, SNTA1, E2F1, TP53INP2, NCOA6, HMGB3L1,
MMP24, UQCC, CEP250, SRC, NNAT, STK4, TP53TG5, MMP9, NCOA5,
CD40, CDH22, TP53RK, NCOA3, B4GALT5, SNAI1, CEBPB, PTPN1,
BCAS4, ATP9A, BCAS1, BMP7, PTK6, SRMS, TNFRSF6B, SAMD10
q11-q13
29-62M
p11.22
39M
ADAM5, ADAM3A
q21.13q24.3
80M146M
ESRP1, CCNE2, TP53INP1, UQCRB, RPL30, SNORA72, STK3, COX6C,
YWHAZ, SAMD12, TNFRSF11B, MYC, TG, SLA, PTK2, GPR20,
LYPD2, CYP11B1, CYP11B2, MAPK15, EPPK1, PARP10
p14-p22.3 0-30M
q22.1
100M
q14.11
q21.33
q22-q31
40-41M
72-73M
74-95M
q32
q33-q34
MMD2, RNF216L, RBAK, WIPI2, SLC29A4, RPA3, CDCA7L, IL6,
CCDC126, STK31, NPY, MPP6, DFNA5, OSBPL3, CYCS, C7orf31, NPVF,
NFE2L3, CBX3, SNX10, SKAP2, CREB5, CPVL, CHN2, PRR15 , NOD1
LRCH4, FBXO24, PCOLCE, MOSPD3, TFR2, GNB2, GIGYF1, POP7,
EPO, ZAN
KIAA0564
C13orf34, DIS3, PIBF1, KLF5, KLF12
LMO7, KCTD12, BTF3L1, CLN5, FBXL3, MYCBP2, SCEL, SLAIN1,
EDNRB, POU4F1, RBM26, SPRY2, GPR180
95-104M STK24, SLC15A1, UBAC2, GPR18, GPR183, FKSG29, TM9SF2, CLYBL,
PCCA, TMTC4
109-115M CARKD, CARS2, ING1, SOX1, ATP11A, F10, ATP4B, GRK1, GAS6,
RASA3, CDC16
chr5
p15.33
0-1M
p13.3-p12 31-45M
CEP72, TPPP, ZDHHC11
CDH6, PDZD2, SPEF2, IL7R, CAPSL, SKP2, GDNF, EGFLAM, LIFR,
DAB2, SEPP1, HMGCS1, CCL28, NNT
chr19
q13.11
32-35M
q13.12-33 35-49M
UQCRFS1, POP4, CCNE1
PDCD5, ANKRD27, SLC7A9, CCDC123, CEBPA, CEBPG, PEPD, GPI,
PDCD2L, WTIP, SCGBL, BCL3, CBLC
chr17
q12
34-36M
q25.3
77M
STARD3, PNMT, PERLD1, ERBB2, GRB7, PSMD3, CSF3, MSL1, CASC3,
CDC6, RARA, GFBP4, TNS4
ANAPC11, NPB, SIRT7, MAFG, LOC92659, PYCR1, NOTUM
chr11
p11.2
q11
q13.3
chr1
q21.2q21.3
45M
PHF21A
55M
OR4C11,OR4P4,OR4S2,OR4C6
68M-69M MRPL21, GHMBP2, CCND1, ORAOV1, FGF19, FGF4, FGF3, ANO1,
FADD
149MSEMA6C, PSMB4, SNX27, TNRC4, MRPL9, OAZ3, LINGO4, RORC,
151M
THEM5, LCE3C, LCE1D
chr3
q26.2q26.31
170M
MDS1, TERC, SAMD7, SEC62, GPR160, PHC3, PRKCI, SKIL, CLDN11,
SLC7A14
chr15
q11.1
18-19M
CXADRP2, POTEB, OR4M2, OR4N4
chr22
q11.21
22M
GSTT1, LOC391322, GSTTP2
chr18
q11.1
17-18M
MIB1, GATA6, CTAGE1
chr6
p21.33
32M
HLA-DRB5
Table 3S Representative deleted genes in loss regions by aCGH analysis.
Chromosome
chr19
Region
Location
Representative Genes
q13.42
56M
SIGLEC14
q13.42
59M
LILRA3, KIR3DP1
q13.43
60M
KIR2DL4
p13.3
0-1M
q11.2
19M
q24.2
73M
HEATR4
q11.22
22M
LOC391322, GSTT1, GSTTP2
q13.1
37M
APOBEC3A, APOBEC3B
p15.4
5M
OR52N5
p15.4
55M
OR4C11, OR4P4, OR4S2,OR4C6
q44
246M
OR2T10, OR2T11, OR2T34
p31.1
71M
NEGR1
p24.1
8M
PTPRD
p21.3
21M
C9orf53, CDKN2A
p14.1
69M
UGT2B17
p26.31
172M
GALNTL6
p21.33
32M
HLA-DRB5
p25.2
3M
HLA-DRB6
q12.2
54M
CES4
q23.1
76M
WWOX
chr17
q21.31
41M
KIAA1267
chr18
q21.1
46M
SMAD4
chr3
p14.2
59M
FHIT
chr14
chr22
chr11
chr1
chr9
chr4
chr6
chr16
KIR2DL2, KIR2DL5A,
KIR2DL5B, KIR3DS1
OR4Q3, OR4M1, OR4N2, OR4K2,
OR4K5, OR4K1
Table 4S. Association of co-gain of MYC and TNFRSF11B with clinicopathological
parameters in gastric cancer patients
Characteristic
Non-gain Signature
Original cohort
20
No. of patient
57.05±9.71
Age at surgery-year
Sex
Male
12
Female
8
Tumor stage
I+II
8
III+IV
12
T stage
1+2
8
3+4
12
N stage
Negative
34
Positive
84
Differentiation
Moderately differentiated
5
Poorly differentiated
15
Vascular invasion
V(-)
10
V(+)
8
Location
Cardia
5
Non-cardia
15
Validation cohort
131
No. of patient
59.64±11.62
Age at surgery-year
Sex
Male
86
Female
45
Tumor stage
I+II
46
III+IV
85
T stage
1+2
24
3+4
107
N stage
Negative
35
Positive
96
Differentiation
Moderately differentiated
34
Poorly differentiated
92
Vascular invasion
V(-)
51
V(+)
71
Location
Cardia
31
Non-cardia
100
Co-gain Signature
21
62.43±8.55
P Value
0.032
17
4
0.232
1
20
0.022
1
20
0.022
27
129
0.023
4
17
0.886
7
14
0.378
7
14
0.764
168
61.05±10.24
<0.001
121
47
0.236
37
131
0.012
13
155
0.006
30
138
0.065
40
122
0.659
56
101
0.296
54
114
0.107
Table 5S Characteristic parameters analysis in two cohorts
Characteristic
aCGH cohort
QGP cohort
P Value
No. of patient (%)
129
384
Age at surgery
60.5
58.4
0.081
Male
94
264
0.378
Female
35
120
I+II
39
122
III+IV
90
262
39
99
90
273
V(-)
50
145
V(+)
72
215
Cardia
39
112
Non-cardia
90
272
Original cohort
Sex
Tumor stage
<0.001
Differentiation
Well-moderately differentiated
Poorly differentiated
0.886
Vascular invasion
0.891
Location
0.818