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Association between polymorphisms in segregation genes BUB1B and TTK and gastric cancer risk

Petra Hudler
Petra Hudler
, 
Nina Kocevar Britovsek
Nina Kocevar Britovsek
, 
Snjezana Frkovic Grazio
Snjezana Frkovic Grazio
 and 
Radovan Komel
Radovan Komel
   | Jul 19, 2016
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Article Category: Research Article
Published Online: Jul 19, 2016
Page range: 297 - 307
Received: Mar 13, 2015
Accepted: Aug 09, 2015
DOI: https://doi.org/10.1515/raon-2015-0047
© 2016 Fazekas and Porvázsnyik, published by De Gruyter Open
This content is free.

Figure 1

Immunoblotting of TTK. (A) Densitometry quantification analysis for the relative band densities from the protein abundance immunoblotting for the indicated protein in the non-tumour (N) and tumour (T) gastric tissues. The p value given (Wilcoxon signed-rank test) indicates the significance of the difference between the non-tumour (N) and tumour (T) gastric tissue samples. (B, C) Densitometry quantification analysis for the relative band densities from the protein abundance immunoblotting for TTK in the non-tumour (N) and tumour (T) gastric tissues samples according to lymph node involvement (pN) and location of the tumours.
Immunoblotting of TTK. (A) Densitometry quantification analysis for the relative band densities from the protein abundance immunoblotting for the indicated protein in the non-tumour (N) and tumour (T) gastric tissues. The p value given (Wilcoxon signed-rank test) indicates the significance of the difference between the non-tumour (N) and tumour (T) gastric tissue samples. (B, C) Densitometry quantification analysis for the relative band densities from the protein abundance immunoblotting for TTK in the non-tumour (N) and tumour (T) gastric tissues samples according to lymph node involvement (pN) and location of the tumours.

Figure 2

Predicted binding sites for transcription factors for polymorphic alleles rs1031963 and rs151658.
Predicted binding sites for transcription factors for polymorphic alleles rs1031963 and rs151658.

Figure 3

Distribution of genotype frequencies of polymorphisms rs151658, rs1031963, and rs1801376 between European populations and Slovenian population.CEU = Utah Residents (CEPH) with Northern and Western European Ancestry; EUR = European population; FIN = Finnish in Finland; GBR = British in England and Scotland; IBS = Iberian Population in Spain; SI (cases) = gastric cancer patients; SI (controls) = control population; SI (total) = combined populations of patients with gastric cancer and healthy controls; TSI = Tuscany in Italy
Distribution of genotype frequencies of polymorphisms rs151658, rs1031963, and rs1801376 between European populations and Slovenian population.CEU = Utah Residents (CEPH) with Northern and Western European Ancestry; EUR = European population; FIN = Finnish in Finland; GBR = British in England and Scotland; IBS = Iberian Population in Spain; SI (cases) = gastric cancer patients; SI (controls) = control population; SI (total) = combined populations of patients with gastric cancer and healthy controls; TSI = Tuscany in Italy

Multivariate survival analysis of clinic-pathological variables in gastric cancer patients

VariableB

Predicted change in the hazard for a unit increase in the predictor.

SE (B)OR (95% CI)P
pN0.6700.1271.954 (1.525-2.504)0.000
Lauren’s classification0.5910.2461.807 (1.116-2.925)0.016

Clinicopathological characteristics of patients with gastric cancer

ParameterNumber of patients (%)
Age (years ± standard deviation) (n = 108)66.12 ± 12.02
Gender (n = 105)
  Male68 (63.0)
  Age (years ± standard deviation) (n = 66)65.07 ± 12.03
  Female40 (37.0)
  Age (years ± standard deviation) (n = 39)67.90 ± 11.94
Lauren’s classification (n = 104)
  Intestinal58 (55.8)
  Diffuse46 (44.2)
Location (n = 101)
  Upper40 (39.6)
  Lower34 (33.7)
  Mixed27 (26.7)
Grade/differentiation (n = 105)
  Well9 (8.6)
  Moderate24 (22.9)
  Poor72 (68.6)
Vascular invasion (n = 80)
  Present27 (33.8)
  Not present53 (66.3)
Perineural invasion (n = 95)
  Present44 (46.3)
  Not present51 (53.7)
Lymphatic invasion (60)
  Present53 (88.3)
  Not present7 (11.7)
pN (n = 105)
  024 (22.9)
  1-215 (14.3)
  3-620 (19.0)
  > 746 (43.8)
pT (n = 105)
  Muscularis propria6 (3.7)
  Subserosa50 (42.6)
  Serosa49 (36.1)

Comparison of TTK rs151658, BUB1B rs1031963, and BUB1B rs1801376 genotypes between the European population and examined groups of Slovenian population

PopulationNGenotype countsP
TTK rs151658
EUR50397 (C|C) / 246 (C|G) / 160 (G|G)χ2 = 8.391; P = 0.015 a χ2 = 11.143; P = 0.004 b NS c
SI (total)a28380 (C|C) / 124 (C|G) / 79 (G|G)
SI (cases)b10836 (C|C) / 48 (C|G) / 24 (G|G)
SI (controls)c17544 (C|C) / 76 (C|G) / 55 (G|G)
BUB1B rs1031963
EUR503125 (C|C) / 259 (C|T) / 119 (T|T)NS d NS e χ2 = 5.715; P = 0.057 f
EUR - male24056 (C|C) / 124 (C|T) / 60 (T|T)_ c _ d χ2 = 6.348; P = 0.042 f
SI (total)d28080 (C|C) / 143 (C|T) / 57 (T|T)
SI (cases - female)e366 (C|C) / 23 (C|T) / 7 (T|T)
SI (cases - male)f6525 (C|C) / 29 (C|T) / 11 (T|T)
BUB1B rs1801376
EUR503240 (A|A) / 217 (A|G) / 46 (G|G)NS g F = 6.569; P = 0.034 h NS 1
EUR - female263135 (A|A) / 109 (A|G) / 19 (G|G)_ g F = 8.277; P = 0.014 h _ i
SI (total)g279136 (A|A) / 118 (A|G) / 25 (G|G)
SI (cases - female)h4011 (A|A) / 25 (A|G) / 4 (G|G)
SI (cases - male)i6836 (A|A) / 24 (A|G) / 8 (G|G)

Comparison of clinic-pathological features and genotypes TTK rs151658, BUB1B rs1031963, and BUB1B rs1801376 in patients with gastric cancer

ParameterSubjectVariant/GenotypeP
TTK rs151658
GGCGCC
Lauren’s classificationIntestinalTotal1721200.049 χ2=6.033
Diffuse52516
IntestinalMale910140.047 χ2=6.113
Diffuse5208
IntestinalFemale81160.024 F=7.499
Diffuse058
BUB1B rs1801376
AAAGGG
IntestinalTotal183370.007
Diffuse28135χ2=9.951
IntestinalMale151440.472 F=1.836
Diffuse2094
IntestinalFemale31930.007 F=9.688
Diffuse841
BUB1B rs1031963
CCCTTT
Tumour differentiationWellTotal144
Moderate7970.035 F=9.642
Poor23397
WellMale023
Moderate6720.139 F=6.439
Poor19206
WellFemale121
Moderate1250.004 F=12.549
Poor19206
BUB1B rs1801376
AAAGGG
pTMuscularispropriaTotal1410.232 F=5.250
Subserosa27185
Serosa18256
MuscularispropriaMale0310.009 F=11.832
Subserosa2262
Serosa13145
MuscularispropriaFemale1100.816 F=1.967
Subserosa5123
Serosa5111
BUB1B rs1801376
AAAGGG
TumourUpperTotal14233
locationLower131560.035 F=10.104
Whole1863

Odds ratios for TTK rs151658, BUB1B rs1031963, and BUB1B rs1801376 between the cases and controls and their effect on gastric cancer risk

Genotype modelCases (n)/Control group (n)OR (95% CI)

p value with Yates correction

PPY
BUB1B rs1031963
Dominant72/1200.900χ2=0.149χ2=0.062
TT+CT vs. CCvs. 32/48(0.527-1.536)0.6990.803
Recessive18/360.797χ2=0.507χ2=0.309
TT vs. CT+CCvs. 86/137(0.426-1.491)0.4760.578
Heterozygous54/890.910χ2=0.108χ2=0.035
CT vs. CCvs. 32/48(0.520-1.594)0.7420.853
Male population
Dominant41/1010.364χ2=9.848χ2=8.834
TT+CT vs. CCvs. 26/26(0.192-0.691)0.0020.003
Recessive11/260.763χ2=0.467χ2=0.241
TT vs. CT+CCvs. 56/101(0.351-1.659)0.4940.623
Heterozygous30/750.400χ2=6.959χ2=6.057
CT vs. CCvs. 26/26(0.201-0.797)0.0080.014
Female population
Dominant31/571.994χ2=1.862χ2=1.281
TT+CT vs. CCvs. 6/22(0.731-5.437)0.1720.258
Recessive7/131.185χ2=0.107χ2=0.004
TT vs. CT+CCvs. 30/66(0.429-3.269)0.7430.949
Heterozygous24/442.000χ2=1.775χ2=1.188
CT vs. CCvs. 6/22(0.714-5.606)0.1830.276
BUB1B rs1801376
Dominant61/821.409χ2=1.927χ2=1.601
GG+AG vs. AAvs. 47/89(0.868-2.287)0.1650.206
Recessive12/131.519χ2=0.999χ2=0.615
GG vs. AA+AGvs. 96/158(0.666-3.465)0.3180.433
Heterozygous49/691.345χ2=1.304χ2=1.025
AG vs. AAvs. 47/89(0.808-2.237)0.2530.311
Malepopulation
Dominant32/460.947χ2=0.029χ2=0.0002
GG+AG vs. AAvs. 36/49(0.508-1.766)0.8640.990
Recessive8/71.676χ2=0.917χ2=0.466
GG vs. AA+AGvs. 60/88(0.577-4.868)0.3380.495
Heterozygous24/390.838χ2=0.272χ2=0.124
AG vs. AAvs. 36/49(0.430-1.630)0.6020.725
Femalepopulation
Dominant29/362.929χ2=6.719χ2=5.737
GG+AG vs. AAvs. 11/40(1.281-6.700)0.0100.017
Recessive4/61.296χ2=0.147χ2=0.001
GG vs. AA+AGvs. 36/70(0.344-4.889)0.7010.971
Heterozygous25/303.030χ2=6.732χ2=5.709
AG vs. AAvs. 11/40(1.292-7.108)0.0090.017

Distribution of genotype frequencies of TTK rs151658, BUB1B rs1031963, and BUB1B rs1801376 between gastric cancer patients and control subjects

VariantsGenotypeCases (n)Controls (n)pHWE (cases)HWE (controls)
TTK rs151658GG2455χ2=3,628 0.163χ2=1.08 0.299χ2=2.87 0.090
CG4876
C/C3644
BUB1B rs1031963CC3248χ2=1.059 0.589χ2=0.345 0.557χ2=0.035 0.852
CT5489
TT1839
BUB1B rs1801376AA4789χ2=2.291 0.318χ2=0.021 0.885χ2=0.005 0.941
AG4969
GG1213
Male populationAA3649χ2=1.186 0.553χ2=1.530 0.216χ2=0.040 0.841
AG2439
GG87
Female populationAA1140F=6.955 0.029χ2=3.352 0.067χ2=0.013 0.909
AG2530
GG46
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