This study aimed at comparison of young-onset versus late-onset BC patients, therefore we performed the analysis of consecutive BRCA1-mutated BC patients to determine relevant thresholds. We analyzed the database of the N.N. Petrov Institute of Oncology (St.-Petersburg, Russia) and identified 771 patients carrying BRCA1 pathogenic variants (median age: 45 years; age range 24–83 years). The analysis of age distribution revealed that patients in the lower quartile were 38 years old or younger, while women in the upper quartile were of >/= 58 years old. These values were selected as the thresholds. DNA for the study was available for 101 young-onset and 45 late-onset BC BRCA1 heterozygous patients from Russia. In addition, 114 young-onset and 63 late-onset cases from Poland satisfied the same criteria. Altogether, HLA genotyping was performed for 215 young-onset and 108 late-onset BC patients carrying BRCA1 pathogenic alleles.
Allele frequencies of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5 genes in early- and late-onset BRCA1-driven BC patients.
Analysis of HLA class I and II loci genotypes was performed in the Polish (PUM, n = 177) and Russian (SPb, n = 146) patients. In order to investigate, whether the pooled analysis of Russian and Polish samples is possible, we statistically compared an age-related spectrum and frequencies of polymorphic alleles between these two groups of patients (Supplementary Table S1, Supplementary Figure S1). No differences were revealed as well as there were no deviations from the Hardy-Weinberg equilibrium at each of the six loci tested.
Allele frequencies (> 1%) of HLA loci are listed in Table 1; the complete dataset is presented in Supplementary Tables S2 and S3. For the HLA-A locus, the A2 serogroup variants accounted for 28.9% of all HLA-A alleles. In total, twenty-seven distinct alleles were identified for the HLA-A locus. Of these, A*02:01P was the most common allele (27.2%), followed by A*01:01P (13.2%), A*03:01P (13.6%), A*24:02P (8.8%), A*25:01P (6.2%), A*11:01P (5.6%), A*26:01P (5.6%). The HLA-B locus showed the highest diversity, with forty-nine identified allelic variants. Allele frequencies of B*07:02P (9.6%), B*08:01P (9.4%), B*15:01P (7.3%), B*35:01P (7.1%), B*18:01P (6.5%), B*44:02P (5.9%), B*27:05P (5.3%) were over 5%. In HLA-C, twenty-two alleles were found at significant frequencies; C*04:01P (13.3%) and C*07:01P (13.5%) were the most common alleles, followed by C*06:02P (10.8%), C*07:02P (10.4%), C*12:03P (8.7%), C*02:02P (6.8%), C*03:04P (6.2%), C*01:02P (5.3%), and C*03:03P (5.3%). In the HLA-DPB1 locus, twenty alleles were identified. DPB1*04:01P (43.5%) was the most common allele, followed by DPB1*02:01P, DPB1*04:02P, DPB1*03:01P with frequencies 15.2%, 15.6%, and 8.8%, respectively; the remaining alleles had lower frequencies (< 5%). Seventeen alleles for the HLA-DQB1 locus were observed at non-zero frequencies. The sum of allele frequencies of DQB1*03 was 33.9%. The DQB1*02:01P, DQB1*05:01P, DQB1*06:02P, DQB1*06:03P and DQB1*05:02P were 20.6%, 13.2%, 10.4%, 7.3% and 5.6%, respectively. There were 31 alleles at the HLA-DRB1 locus, making it very diverse. DRB1*01:01P, DRB1*03:01P, DRB1*07:01P, and DRB1*15:01P were the most frequent (11–12%), followed by DRB1*04:01P, DRB1*11:01P, DRB1*11:04P, and DRB1*13:01P (5–7%).
Table 1
Allele frequencies of HLA loci in groups of early-onset (≤ 38 y.o., “young”) and late-onset patients (≥ 58 y.o., “senior”) with BRCA1-driven breast cancer
HLA locus
|
Allele
|
n
|
%
646 alleles (323 patients)
|
Young (n alleles)
|
Senior (n alleles)
|
Young (%) 430 alleles (215 patients)
|
Senior (%) 216 alleles (108 patients)
|
P-value
|
HLA-A
|
1:01P
|
85
|
13.2%
|
56
|
29
|
13.02%
|
13.43%
|
ns
|
HLA-A
|
2:01P
|
176
|
27.2%
|
120
|
56
|
27.91%
|
25.93%
|
ns
|
HLA-A
|
3:01P
|
88
|
13.6%
|
59
|
29
|
13.72%
|
13.43%
|
ns
|
HLA-A
|
11:01P
|
36
|
5.6%
|
19
|
17
|
4.42%
|
7.87%
|
0.071
|
HLA-A
|
23:01P
|
8
|
1.2%
|
6
|
2
|
1.40%
|
0.93%
|
ns
|
HLA-A
|
24:02P
|
57
|
8.8%
|
41
|
16
|
9.53%
|
7.41%
|
ns
|
HLA-A
|
25:01P
|
40
|
6.2%
|
24
|
16
|
5.58%
|
7.41%
|
ns
|
HLA-A
|
26:01P
|
36
|
5.6%
|
22
|
14
|
5.12%
|
6.48%
|
ns
|
HLA-A
|
30:01P
|
16
|
2.5%
|
9
|
7
|
2.09%
|
3.24%
|
ns
|
HLA-A
|
31:01P
|
16
|
2.5%
|
14
|
2
|
3.26%
|
0.93%
|
0.105
|
HLA-A
|
32:01P
|
28
|
4.3%
|
19
|
9
|
4.42%
|
4.17%
|
ns
|
HLA-A
|
33:01P
|
7
|
1.1%
|
6
|
1
|
1.40%
|
0.46%
|
ns
|
HLA-A
|
66:01P
|
7
|
1.1%
|
4
|
3
|
0.93%
|
1.39%
|
ns
|
HLA-A
|
68:01P
|
19
|
2.9%
|
13
|
6
|
3.02%
|
2.78%
|
ns
|
HLA-B
|
7:02P
|
62
|
9.6%
|
39
|
23
|
9.07%
|
10.65%
|
ns
|
HLA-B
|
8:01P
|
61
|
9.4%
|
43
|
18
|
10.00%
|
8.33%
|
ns
|
HLA-B
|
13:02P
|
28
|
4.3%
|
16
|
12
|
3.72%
|
5.56%
|
ns
|
HLA-B
|
14:02P
|
12
|
1.9%
|
9
|
3
|
2.09%
|
1.39%
|
ns
|
HLA-B
|
15:01P
|
47
|
7.3%
|
29
|
18
|
6.74%
|
8.33%
|
ns
|
HLA-B
|
18:01P
|
42
|
6.5%
|
29
|
13
|
6.74%
|
6.02%
|
ns
|
HLA-B
|
27:02P
|
8
|
1.2%
|
4
|
4
|
0.93%
|
1.85%
|
ns
|
HLA-B
|
27:05P
|
34
|
5.3%
|
21
|
13
|
4.88%
|
6.02%
|
ns
|
HLA-B
|
35:01P
|
46
|
7.1%
|
30
|
16
|
6.98%
|
7.41%
|
ns
|
HLA-B
|
35:02P
|
7
|
1.1%
|
5
|
2
|
1.16%
|
0.93%
|
ns
|
HLA-B
|
35:03P
|
20
|
3.1%
|
13
|
7
|
3.02%
|
3.24%
|
ns
|
HLA-B
|
37:01P
|
10
|
1.5%
|
4
|
6
|
0.93%
|
2.78%
|
ns
|
HLA-B
|
38:01P
|
18
|
2.8%
|
11
|
7
|
2.56%
|
3.24%
|
ns
|
HLA-B
|
40:01P
|
23
|
3.6%
|
19
|
4
|
4.42%
|
1.85%
|
0.117
|
HLA-B
|
40:02P
|
12
|
1.9%
|
9
|
3
|
2.09%
|
1.39%
|
ns
|
HLA-B
|
41:02P
|
17
|
2.6%
|
12
|
5
|
2.79%
|
2.31%
|
ns
|
HLA-B
|
44:02P
|
38
|
5.9%
|
29
|
9
|
6.74%
|
4.17%
|
ns
|
HLA-B
|
44:03P
|
22
|
3.4%
|
15
|
7
|
3.49%
|
3.24%
|
ns
|
HLA-B
|
51:01P
|
27
|
4.2%
|
18
|
9
|
4.19%
|
4.17%
|
ns
|
HLA-B
|
52:01P
|
9
|
1.4%
|
6
|
3
|
1.40%
|
1.39%
|
ns
|
HLA-B
|
55:01P
|
8
|
1.2%
|
5
|
3
|
1.16%
|
1.39%
|
ns
|
HLA-B
|
56:01P
|
13
|
2.0%
|
10
|
3
|
2.33%
|
1.39%
|
ns
|
HLA-B
|
57:01P
|
21
|
3.3%
|
15
|
6
|
3.49%
|
2.78%
|
ns
|
HLA-C
|
1:02P
|
34
|
5.3%
|
22
|
12
|
5.12%
|
5.56%
|
ns
|
HLA-C
|
2:02P
|
44
|
6.8%
|
31
|
13
|
7.21%
|
6.02%
|
ns
|
HLA-C
|
3:03P
|
34
|
5.3%
|
17
|
17
|
3.95%
|
7.87%
|
ns
|
HLA-C
|
3:04P
|
40
|
6.2%
|
33
|
7
|
7.67%
|
3.24%
|
0.027
|
HLA-C
|
4:01P
|
86
|
13.3%
|
60
|
26
|
13.95%
|
12.04%
|
ns
|
HLA-C
|
5:01P
|
24
|
3.7%
|
15
|
9
|
3.49%
|
4.17%
|
ns
|
HLA-C
|
6:02P
|
70
|
10.8%
|
41
|
29
|
9.53%
|
13.43%
|
ns
|
HLA-C
|
7:01P
|
87
|
13.5%
|
57
|
30
|
13.26%
|
13.89%
|
ns
|
HLA-C
|
7:02P
|
67
|
10.4%
|
42
|
25
|
9.77%
|
11.57%
|
ns
|
HLA-C
|
7:04P
|
17
|
2.6%
|
15
|
2
|
3.49%
|
0.93%
|
0.068
|
HLA-C
|
8:02P
|
17
|
2.6%
|
11
|
6
|
2.56%
|
2.78%
|
ns
|
HLA-C
|
12:02P
|
9
|
1.4%
|
6
|
3
|
1.40%
|
1.39%
|
ns
|
HLA-C
|
12:03P
|
56
|
8.7%
|
38
|
18
|
8.84%
|
8.33%
|
ns
|
HLA-C
|
15:02P
|
13
|
2.0%
|
7
|
6
|
1.63%
|
2.78%
|
ns
|
HLA-C
|
15:05P
|
7
|
1.1%
|
5
|
2
|
1.16%
|
0.93%
|
ns
|
HLA-C
|
17:01P
|
21
|
3.3%
|
14
|
7
|
3.26%
|
3.24%
|
ns
|
HLA-DPB1
|
1:01P
|
30
|
4.6%
|
21
|
9
|
4.88%
|
4.17%
|
ns
|
HLA-DPB1
|
2:01P
|
98
|
15.2%
|
67
|
31
|
15.58%
|
14.35%
|
ns
|
HLA-DPB1
|
3:01P
|
57
|
8.8%
|
38
|
19
|
8.84%
|
8.80%
|
ns
|
HLA-DPB1
|
4:01P
|
281
|
43.5%
|
185
|
96
|
43.02%
|
44.44%
|
ns
|
HLA-DPB1
|
4:02P
|
101
|
15.6%
|
67
|
34
|
15.58%
|
15.74%
|
ns
|
HLA-DPB1
|
6:01P
|
15
|
2.3%
|
12
|
3
|
2.79%
|
1.39%
|
ns
|
HLA-DPB1
|
13:01P
|
13
|
2.0%
|
9
|
4
|
2.09%
|
1.85%
|
ns
|
HLA-DPB1
|
14:01P
|
9
|
1.4%
|
4
|
5
|
0.93%
|
2.31%
|
ns
|
HLA-DPB1
|
23:01P
|
9
|
1.4%
|
7
|
2
|
1.63%
|
0.93%
|
ns
|
HLA-DQB1
|
2:01P
|
133
|
20.6%
|
85
|
48
|
19.77%
|
22.22%
|
ns
|
HLA-DQB1
|
3:01P
|
136
|
21.1%
|
89
|
47
|
20.70%
|
21.76%
|
ns
|
HLA-DQB1
|
3:02P
|
54
|
8.4%
|
41
|
13
|
9.53%
|
6.02%
|
ns
|
HLA-DQB1
|
3:03P
|
23
|
3.6%
|
16
|
7
|
3.72%
|
3.24%
|
ns
|
HLA-DQB1
|
4:02P
|
26
|
4.0%
|
18
|
8
|
4.19%
|
3.70%
|
ns
|
HLA-DQB1
|
5:01P
|
85
|
13.2%
|
61
|
24
|
14.19%
|
11.11%
|
ns
|
HLA-DQB1
|
5:02P
|
36
|
5.6%
|
25
|
11
|
5.81%
|
5.09%
|
ns
|
HLA-DQB1
|
5:03P
|
12
|
1.9%
|
10
|
2
|
2.33%
|
0.93%
|
ns
|
HLA-DQB1
|
6:02P
|
67
|
10.4%
|
45
|
22
|
10.47%
|
10.19%
|
ns
|
HLA-DQB1
|
6:03P
|
47
|
7.3%
|
22
|
25
|
5.12%
|
11.57%
|
0.003
|
HLA-DQB1
|
6:09P
|
15
|
2.3%
|
11
|
4
|
2.56%
|
1.85%
|
ns
|
HLA-DRB1
|
1:01P
|
75
|
11.6%
|
53
|
22
|
12.33%
|
10.19%
|
ns
|
HLA-DRB1
|
03:01P
|
77
|
11.9%
|
53
|
24
|
12.33%
|
11.11%
|
ns
|
HLA-DRB1
|
4:01P
|
35
|
5.4%
|
19
|
16
|
4.42%
|
7.41%
|
ns
|
HLA-DRB1
|
4:02P
|
10
|
1.5%
|
9
|
1
|
2.09%
|
0.46%
|
ns
|
HLA-DRB1
|
4:04P
|
13
|
2.0%
|
10
|
3
|
2.33%
|
1.39%
|
ns
|
HLA-DRB1
|
7:01P
|
76
|
11.8%
|
48
|
28
|
11.16%
|
12.96%
|
ns
|
HLA-DRB1
|
8:01P
|
25
|
3.9%
|
18
|
7
|
4.19%
|
3.24%
|
ns
|
HLA-DRB1
|
11:01P
|
47
|
7.3%
|
32
|
15
|
7.44%
|
6.94%
|
ns
|
HLA-DRB1
|
11:04P
|
32
|
5.0%
|
20
|
12
|
4.65%
|
5.56%
|
ns
|
HLA-DRB1
|
12:01P
|
15
|
2.3%
|
12
|
3
|
2.79%
|
1.39%
|
ns
|
HLA-DRB1
|
13:01P
|
44
|
6.8%
|
23
|
21
|
5.35%
|
9.72%
|
0.037
|
HLA-DRB1
|
13:02P
|
15
|
2.3%
|
11
|
4
|
2.56%
|
1.85%
|
ns
|
HLA-DRB1
|
13:03P
|
21
|
3.3%
|
15
|
6
|
3.49%
|
2.78%
|
ns
|
HLA-DRB1
|
14:01P
|
11
|
1.7%
|
9
|
2
|
2.09%
|
0.93%
|
ns
|
HLA-DRB1
|
15:01P
|
73
|
11.3%
|
46
|
27
|
10.70%
|
12.50%
|
ns
|
HLA-DRB1
|
16:01P
|
31
|
4.8%
|
22
|
9
|
5.12%
|
4.17%
|
ns
|
|
|
|
N = 620***
|
|
|
N = 408
|
N = 212
|
|
HLA-DRB3
|
DRB3 1:01P
|
164
|
26.45%
|
108
|
56
|
26.47%
|
26.42%
|
ns
|
HLA-DRB3
|
DRB3 2:02P
|
159
|
25.65%
|
107
|
52
|
26.23%
|
24.53%
|
ns
|
HLA-DRB3
|
DRB3 3:01P
|
18
|
2.90%
|
14
|
4
|
3.43%
|
1.89%
|
ns
|
HLA-DRB4
|
DRB4 1:01P
|
155
|
25.00%
|
99
|
56
|
24.26%
|
26.42%
|
ns
|
HLA-DRB5
|
DRB5 1:01P
|
83
|
13.39%
|
52
|
31
|
12.75%
|
14.62%
|
ns
|
HLA-DRB5
|
DRB5 2:02P
|
32
|
5.16%
|
23
|
9
|
5.64%
|
4.25%
|
ns
|
P-values for allele frequencies comparison were calculated with the use of Fisher exact test or Chi square test for 2x2 table analysis. |
*HLA-DRB3/4/5 genotype data were not available for 13 subjects. |
This table includes only alleles with MAF > 1%; the complete set of data is given in Supplementary Table S3. |
Analysis of the distribution of HLA class I and II alleles in young-onset vs. late-onset BC patients showed a significant increase in the frequency of the HLA-C*3:04P allele in the “young” group [7.67% vs. 3.24% (p = 0.027, Chi square test)], while HLA-DQB1*6:03P and HLA-DRB1*13:01P alleles were more prevalent in the “elderly” group [13.8% vs. 5.1% (p = 0.0001) and 9.7% vs. 5.4% (p = 0.037), respectively, Chi square test] (Fig. 1). The “protective” effect of the HLA-DQB1*06:03P remained statistically valid after the adjustment for multiple comparisons (FDR correction) [OR 2.91 (95% CI 1.62–5.22), p = 0.0003]. Increased prevalence of the HLA-DQB1*06:03P variant in the late-onset group was attributed both to the excess of allele carriers [25/108 (23.1%) vs. 22/215 (10.2%), OR 2.64 (95% CI 1.41–4.95), p = 0.002, Chi square test] and to overrepresentation of homozygous genotypes [3/108 (2.8%) vs. 0/215 (0%), p = 0.08, Fisher exact test]. Stratification of the sample set into two populations, Russian and Polish, revealed identical trends in both cohorts [adjusted OR 2.96, 95% CI 1.58–5.56; p < 0.001, Mantel-Haenszel test] (Table 2).
Table 2
Prevalence of HLA-DQB1*06:03P allele in young- ad late-onset BRCA1-driven BC patients: analysis of two Slavic populations
Cohorts
|
Age group
|
N
patients
|
DQB1*N/N
|
DQB1*N/
06:03P
|
DQB1*
06:03P/
06:03P
|
P-value
(for 06:03P homozygotes)
|
DQB1
*06:03P carriers
|
P-value (for DQB1
*06:03P carriers)
|
N
alleles
|
HLA-DQB1
*06:03P
|
HLA-DQB1*N
|
P-value (for DQB1
*06:03P allele)
|
Total
|
Young
(≤ 38 y.o.)
|
215
|
193 (89.8%)
|
22 (10.2%)
|
0
(0%)
|
0.037
|
22
(10.2%)
|
0.003
|
430
|
22
(5.1%)
|
408
(94.9%)
|
0.0001
|
|
Senior
(≥ 58 y.o.)
|
108
|
83 (76.9%)
|
22 (20.3%)
|
3
(2.8%)
|
25
(23.1%)
|
216
|
28
(13.0%)
|
188
(87.0%)
|
|
OR (95% CI)
|
|
14.3
(0.73–279.27)
|
0.080
|
2.64
(1.41–4.95)
|
0.002
|
|
2.91
(1.62–5.22)
|
0.0003
|
SPb
|
Young
(≤ 38 y.o.)
|
101
|
92 (91.2%)
|
9 (8.9%)
|
0
(0%)
|
0.308
|
9
(8.9%)
|
0.005
|
202
|
9
(4.5%)
|
193
(95.5%)
|
0.0001
|
|
Senior
(≥ 58 y.o.)
|
45
|
32 (71.1%)
|
12 (26.7%)
|
1
(2%)
|
13
(28.9%)
|
90
|
14
(15.6%)
|
76
(84.4%)
|
|
OR (95% CI)
|
|
6.84
(0.27–171.25)
|
0.177
|
5.78
(2.2–15.16)
|
< 0.001
|
|
3.95
(1.64–9.51)
|
0.002
|
PUM
|
Young
(≤ 38 y.o.)
|
114
|
101 (88.5%)
|
13 (11.4%)
|
0
(0%)
|
0.125
|
13
(11.4%)
|
0.181
|
228
|
13
(5.7%)
|
215
(94.3%)
|
0.0001
|
|
Senior
(≥ 58 y.o.)
|
63
|
51 (81.0%)
|
10 (15.9%)
|
2
(3.2%)
|
13
(20.6%)
|
126
|
14
(11.1%)
|
112
(88.9%)
|
|
OR (95% CI)
|
|
9.31
(0.44–196.98)
|
0.083
|
1.83
(0.78–4.29)
|
0.241
|
|
2.07
(0.94–4.55)
|
0.066
|
|
OR (95% CI)
M-H adjusted
|
|
|
|
8.16
(0.89–74.57)
|
0.028
|
2.96
(1.58–5.56)
|
< 0.001
|
|
2.75
(1.54–4.93)
|
0.0001
|
Notes: Fisher exact test was used for comparison of genotype proportions in two age groups, Mantel-Haenszel Chi-squared test was applied for analysis of stratified tables [https://epitools.ausvet.com.au/mantelhaenszel] |
The analysis of HLA supertypes did not reveal additional genetic determinants associated with age-related BRCA1 penetrance (Supplementary Table S3).
Distribution of homozygous HLA-genotypes in young-onset and late-onset patients with BRCA1-driven BC.
HLA class I/II homozygous genotype frequencies were compared in early- and late-onset BC patients. For all HLA-I loci, we detected a consistent trend towards an increase in the number of homozygous genotypes in the early-onset group (Table 3, Fig. 2). This trend reached the level of statistical significance for the HLA-A locus [14.4% vs. 6.5% (p = 0.037, Chi square test), OR 2.4 (95% CI 1.03–5.72), p = 0.042]. For HLA-A and -B class I genotypes, we considered not only true homozygotes, but also so-called "functional" homozygotes, which are defined as combinations of two alleles from the same supertype (i.e., not identical, but having the similar main anchor specificity and ability to present neoantigens) [28]. The mentioned tendency remained true for "functional" homozygotes, but the differences between age groups did not reach the threshold for statistical significance (Table 3, Fig. 2).
Table 3
Distribution of HLA class I/II homozygous genotypes in different age groups of BRCA1-driven BC patients
HLA I, II germline status
|
Young ≤ 38
y.o.
|
Senior ≥ 58
y.o.
|
Young ≤ 38
y.o.
|
Senior ≥ 58
y.o.
|
Young ≤ 38
y.o.
|
Senior ≥ 58
y.o.
|
Fisher/ Xsq
|
|
homo %
|
homo %
|
homo
|
homo
|
hetero
|
hetero
|
P-value
|
HLA-I class loci:
|
N = 215
|
N = 108
|
|
|
|
|
|
HLA-A homozygotes (allele)
|
14.4
|
6.5
|
31
|
7
|
184
|
101
|
0.037
|
HLA-A homozygotes (supertype)
|
24.7
|
21.3
|
53
|
23
|
162
|
85
|
0.580
|
HLA-B homozygotes (allele)
|
5.6
|
4.6
|
12
|
5
|
203
|
103
|
0.798
|
HLA-B homozygotes (supertype)
|
24.2
|
16.7
|
52
|
18
|
163
|
90
|
0.122
|
HLA-C homozygotes (allele)
|
10.2
|
7.4
|
22
|
8
|
193
|
100
|
0.543
|
HLA-C homozygotes (supertype)
|
16.3
|
11.1
|
35
|
12
|
180
|
96
|
0.214
|
At least one homozygous HLA-I locus (allele)
|
19.1
|
13.9
|
41
|
15
|
174
|
93
|
0.246
|
At least one homozygous HLA-I locus (supertype)
|
47.4
|
38.9
|
102
|
42
|
113
|
66
|
0.145
|
> 1 homozygous HLA-I loci (allele)
|
7.9
|
3.7
|
17
|
4
|
198
|
104
|
0.230
|
> 1 homozygous HLA-I loci (supertype)
|
13.0
|
9.3
|
28
|
10
|
187
|
98
|
0.419
|
3 homozygous HLA-I loci (allele)
|
3.3
|
0.9
|
7
|
1
|
208
|
107
|
0.276
|
3 homozygous HLA-I loci (supertype)
|
4.7
|
0.9
|
10
|
1
|
205
|
107
|
0.107
|
HLA-II class loci:
|
N = 215
|
N = 108
|
|
|
|
|
|
HLA-DPB1 homozygotes (allele)
|
22.4
|
22.3
|
48
|
24
|
167
|
84
|
ns
|
HLA-DPB1 homozygotes (supertype)
|
35.4
|
37.1
|
76
|
40
|
139
|
68
|
ns
|
HLA-DQB1 homozygotes (allele)
|
15.8
|
15.7
|
34
|
17
|
181
|
91
|
ns
|
HLA-DQB1 homozygotes (supertype)
|
28.8
|
24.1
|
62
|
26
|
153
|
82
|
0.364
|
HLA-DRB1 homozygotes (allele)
|
11.7
|
6.5
|
25
|
7
|
190
|
101
|
0.144
|
HLA-DRB1 homozygotes (supertype)
|
13.5
|
7.4
|
29
|
8
|
186
|
100
|
0.105
|
HLA-DRB3/4/5 zero genotype
|
5.1
|
1.9
|
11
|
2
|
204
|
106
|
0.232
|
|
N = 204*
|
N = 106*
|
|
|
|
|
|
HLA-DRB3/4/5 homozygotes (allele)
|
53.9
|
51.9
|
110
|
55
|
94
|
51
|
ns
|
HLA-DRB3/4/5 homozygotes (supertype)
|
54.4
|
51.9
|
111
|
55
|
93
|
51
|
ns
|
|
N = 215
|
N = 108
|
|
|
|
|
|
At least one homozygous HLA-II locus (allele)
|
66.5
|
69.4
|
143
|
75
|
72
|
33
|
ns
|
At least one homozygous HLA-II locus (supertype)
|
78.1
|
78.7
|
168
|
85
|
47
|
23
|
ns
|
|
N = 204*
|
N = 106*
|
|
|
|
|
|
> 1 homozygous HLA-II loci (allele)
|
22.5
|
17.9
|
46
|
19
|
158
|
87
|
0.342
|
> 1 homozygous HLA-II loci (supertype)
|
34.8
|
26.4
|
71
|
28
|
133
|
78
|
0.157
|
|
N = 215
|
N = 108
|
|
|
|
|
|
At least one homozygous HLA-I, II locus (allele)
|
71.6
|
73.1
|
154
|
79
|
61
|
29
|
ns
|
At least one homozygous HLA locus (supertype)
|
87.4
|
87.0
|
188
|
94
|
27
|
14
|
ns
|
|
N = 204*
|
N = 106*
|
|
|
|
|
|
> 1 homozygous HLA-I, II loci (allele)
|
31.4
|
25.5
|
64
|
27
|
140
|
79
|
0.279
|
> 1 homozygous HLA-I, II loci (supertype)
|
55.9
|
45.3
|
114
|
48
|
90
|
58
|
0.076
|
> 3 homozygous HLA-I, II loci (allele)
|
5.9
|
2.8
|
12
|
3
|
192
|
103
|
0.279
|
> 3 homozygous HLA-I, II loci (supertype)
|
12.7
|
7.5
|
26
|
8
|
178
|
98
|
0.107
|
> 5 homozygous HLA-I, II loci (allele)
|
2.9
|
0.0
|
6
|
0
|
198
|
106
|
0.098
|
> 5 homozygous HLA-I, II loci (supertype)
|
2.9
|
0.0
|
6
|
0
|
198
|
106
|
0.098
|
Notes: * For 13 patients, no information about the genotype of the locus HLA-DRB3/4/5 was available; these cases were excluded from the statistical analysis of "cumulative" homozygosity. |
The frequencies of HLA-DPB1, HLA-DQB1 and HLA-DRB3/4/5 homozygous genotypes did not significantly differ between the young-onset and the late-onset BC patients. There was a trend towards the increased frequency of DRB1 homozygotes in the young-onset vs. late-onset patients [11.7% vs. 6.5% (p = 0.144, Fisher exact test)]. This trend remained when missense alleles belonging to same serogroup were considered as one supertype [13.5% vs. 7.4% (p = 0.105, Fisher exact test)] [29].
None of the analyzed women were homozygous for all 7 HLA class I/II loci analyzed. However, 6 BC patients demonstrated homozygosity for 6 out of 7 HLA class I/II loci. Strikingly, all these six women were diagnosed with BC at the age of </= 38 years [OR = 6.97 (95% CI 0.39–125.01), p = 0.187].