Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Sofia Khan; Rainer Fagerholm; Sajjad Rafiq; William Tapper; Kristiina Aittomäki; Jianjun Liu; Carl Blomqvist; Diana Eccles; Heli Nevanlinna

doi:10.1158/1078-0432.CCR-15-0296

DOI: 10.1158/1078-0432.CCR-15-0296 Published September 2015

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Figure 1.
The Kaplan–Meier plots of cumulative breast cancer–specific 10-year survival of rs8113308 genotypes (A) in a pooled stage I (HEBCS + POSH GWS) data among ER-positive patients receiving endocrine therapy; (B) in HEBCS GWS data among ER-positive patients not receiving endocrine therapy; (C) in a pooled stage I (HEBCS + POSH GWS) data among ER-negative patients. Number of patients at risk is presented under each Kaplan–Meier plot.
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Figure 2.
Forest plots of HRs and their CIs for the SNP rs8113308 in the entire sample set and within phenotype- and treatment-based subgroups separately in each of the four studies. The Cox proportional hazards models were used to derive HR for breast cancer–specific mortality in HEBCS GWS, POSH GWS, and POSH validation and for all-cause mortality for SUCCESS-A.
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Figure 3.
ZNF350 mRNA levels by genotype using Metabric data (A) and gene expression-based disease-free survival of ZNF350 using online web-based service BreastMark (B–D). A, boxplot of ZNF350 mRNA levels by SNP rs11881650 (a tag SNP for rs8113308; r² = 0.81) genotype (0 = common homozygote, 1 = heterozygote, 2 = rare homozygote). *, Wilcoxon rank-sum test for common homozygote versus rare homozygote, P = 0.018 in ER-positive tumors. Survival in (B) ER-positive patients receiving tamoxifen treatment (N = 614, events = 149), (C) ER-positive patients not receiving tamoxifen treatment (N = 1,376, events = 451), and (D) ER-negative patients (N = 423, events = 197). The cutoff for expression level was set to high, that is, the top 25% expression level based on the inter quartile range. The follow-up time was not adjustable.

Table 1.

Age and tumor characteristics of study participants from HEBCS and POSH GWS, POSH validation, and SUCCESS-A

Characteristics	HEBCS GWS	POSH GWS	POSH Validation	SUCCESS-A
Number of cases	805	536	1,415	3,596
Vital status
Alive	466 (58%)	300 (56%)	1,194 (84%)	3,389 (94%)
Deceased: all-cause	339 (42%)	236 (44%)	221 (16%)	207 (6%)
Deceased: BC-specific	312 (39%)	235 (44%)	208 (15%)	NA
Follow-up mean ± SD	10.6 ± 6.6	4.1 ± 2.0	5.0 ± 1.9	3.9 ± 1.7
Age, mean [range], y	54.1 [22–87]	35.8 [18–41]	35.8 [18–40]	53.6 [19–85]
ER
Negative	230 (29%)	370 (69%)	318 (22%)	1,106 (31%)
Positive	513 (64%)	165 (31%)	1,089 (77%)	2,458 (68%)
Missing, n.	62 (8%)	1 (0.2%)	8 (1%)	32 (1%)
Grade
1	144 (18%)	13 (2%)	106 (7%)	165 (5%)
2	312 (39%)	84 (16%)	549 (39%)	1,698 (47%)
3	280 (35%)	422 (79%)	726 (51%)	1,698 (47%)
Missing, n.	69 (9%)	17 (3%)	34 (2%)	35 (1%)
T
1	390 (48%)	232 (43%)	692 (49%)	1,464 (41%)
2	304 (38%)	236 (44%)	493 (35%)	1,856 (52%)
3	50 (6%)	49 (9%)	49 (3%)	192 (5%)
4	47 (6%)	12 (2%)	34 (2%)	50 (1%)
Missing, n.	14 (2%)	7 (1%)	147 (10%)	34* (1%)
N
Negative	338 (42%)	248 (46%)	654 (46%)	1,248 (35%)
Positive	446 (55%)	262 (49%)	742 (52%)	2,311 (64%)
Missing, n.	21 (3%)	26 (5%)	19 (1%)	37 (1%)
M
Negative	740 (92%)	481 (90%)	1,398 (99%)	3,487 (97%)
Positive	57 (7%)	50 (9%)	10 (0.7%)	4 (0.1%)
Missing, n.	8 (1%)	5 (1%)	7 (0.3%)	105 (2.9%)
Adjuvant chemotherapy treatment^a	364 (45%)	518 (96.6%)	1,018 (72%)	3,596 (100%)
A&T	14 (2%)	129 (24%)	187 (18%)	—
Antracyclines	191 (24%)	376 (70%)	817 (80%)	3,596 (100%)
Taxanes	2 (0.2%)	8 (1.5%)	5 (0.5%)	—
CMF	153 (19%)	4 (1%)	9 (1%)	—
Adjuvant Endocrine treatment^a^,^b	240 (29.8%)	155 (29%)	1,027 (72.6%)	2,458 (68%)
Anti-estrogen (Tamoxifen)	234 (29%)	145 (27%)	966 (68%)	2,458 (68%)
Aromatase inhibitor	6 (20.7%)	9 (1.7%)	33 (2%)	223 (6%)
LHRH agonist	0	49 (9%)	250 (17.7%)	29 (1%)
No endocrine treatment (tamoxifen/AI/LHRH agonist)	272 (34%)	10 (1.8%)	57 (4%)	0

Abbreviations: NA, not available; T, tumor size according to TNM classification; N, metastasis to lymph node; M, distant metastasis.

↵^aThe total numbers may not add up, because a patient may have received several types of adjuvant chemotherapy/endocrine treatment.
↵^bAmong ER-positive patients.

Table 2.

Stage I and II meta-analysis of univariate Cox regression analysis results for the four associations in stage I and II

ER-positive patients receiving endocrine treatment
SNP	Chr:position^a	MAF^b	HEBCS GWS HR (95% CI)	HEBCS GWS P	POSH GWS HR (95% CI)	POSH GWS P	POSH val. HR (95% CI)	POSH val. P	Success-A HR (95% CI)	Success-A P	Meta-analysis HR (95% CI)	Meta-analysis P	Location
rs8113308	19:52445386	0.152	1.72 (1.08–2.72)	0.022	2.17 (1.37–3.45)	9.81 × 10⁻⁴	1.45 (1.04–2.02)	0.030	1.72 (1.11–2.68)	0.015	1.69 (1.37–2.07)	6.34 × 10⁻⁷	ZNF613
rs4082843	4:7109083	0.164	0,40 (0.23–0.67)	6.50 × 10⁻⁴	0,36 (0.15–0.82)	0.015	1,07 (0.75–1.51)	0,484	—	—	0.72 (0.55–0.95)	2.18 × 10⁻²	GRPEL1 \| SORCS2
rs4767413	12:116951069	0.178	2,06 (1.41–3.01)	1.90 × 10⁻⁴	1,67 (1.08–2.57)	0.021	1,13 (0.82–1.56)	0,328	1.07 (0.73–1.58)	0.721	1.39 (1.15–1.67)	5.86 × 10⁻⁴	MED13L \| LINC00173
rs11085098	19:4784553	0.307	1,76 (1.25–2.47)	0.001	1,61 (1.11–2.33)	0.012	0,92 (0.69–1.22)	0,242	0.83 (0.59–1.17)	0.277	1.16 (0.99–1.37)	7.02 × 10⁻²	MIR7–3HG \| FEM1A
ER-positive patients not receiving endocrine treatment
SNP	Chr:position^a	MAF^b	HEBCS GWS HR (95% CI)	HEBCS GWS P	POSH GWS HR (95% CI)	POSH GWS P	POSH val. HR (95% CI)	POSH val. P	Success-A HR (95% CI)	Success-A P	Meta-analysis HR (95% CI)	Meta-analysis P	Location
rs8113308	19:52445386	0.152	0.66 (0.40–1.07)	0.093	—	—	—	—	—	—	—	—	ZNF613
rs4082843	4:7109083	0.164	1.15 (0.78–1.70	0,486	—	—	—	—	—	—	—	—	GRPEL1 \| SORCS2
rs4767413	12:116951069	0.178	0.91 (0.56–1.48)	0,712	—	—	—	—	—	—	—	—	MED13L \| LINC00173
rs11085098	19:4784553	0.307	1.01 (0.70–1.46)	0,963	—	—	—	—	—	—	—	—	MIR7–3HG \| FEM1A
ER-negative patients
SNP	Chr:position^a	MAF^b	HEBCS GWS HR (95% CI)	HEBCS GWS P	POSH GWS HR (95% CI)	POSH GWS P	POSH val. HR (95% CI)	POSH val. P	Success-A HR (95% CI)	Success-A P	Meta-analysis HR (95% CI)	Meta-analysis P	Location
rs8113308	19:52445386	0.152	0.65 (0.42–1.03)	0.064	0.71 (0.46–1.09)	0.121	0.93 (0.46–1.88)	0.842	0.49 (0.26–0.93)	0.029	0.71 (0.56–0.91)	6.00 × 10⁻³	ZNF613
rs4082843	4:7109083	0.164	1,06 (0.73–1.52)	0.765	1,00 (0.73–1.37)	0.978	0,80 (0.38–1.67)	0.346	—	—	1.00 (0.80–1.26)	0.984	GRPEL1 \| SORCS2
rs4767413	12:116951069	0.178	1,01 (0.64–1.61)	0.958	1,04 (0.76–1.42)	0.806	1,44 (0.80–2.58	0.148	0.98 (0.72–1.34)	0.652	1.09 (0.89–1.33)	0.400	MED13L \| LINC00173
rs11085098	19:4784553	0.307	0,88 (0.64–1.21)	0.428	1,00 (0.77–1.29)	0.978	0,91 (0.56–1.47)	0.460	1.09 (0.75–1.59)	0.896	0.95 (0.81–1.12)	0.544	MIR7-3HG \| FEM1A

NOTE: The table presents per study as well as the meta-analysis results in ER-positive patients receiving endocrine treatment, ER-positive patients not receiving endocrine treatment, and ER-negative patients. The per study results in ER-positive patients not receiving endocrine treatment are only presented for HEBCS, because very few ER-positive patients did not receive endocrine treatment in POSH GWS, POSH validation, and SUCCESS-A. For SNPs rs4082843, there was no exact SNP match or a tag SNP with r² > 0.8 available in SUCCESS-A data.

↵^aAccording to the human genome build 36.
↵^bMAF in Caucasian of European descent.

Table 3.

The Cox proportional hazards models to test for interaction between endocrine treatment and rs8113308 in the pooled dataset of HEBCS and POSH GWS and POSH validation

Per allele model assuming no interaction
Covariate	HR (95% CI)	P
Per-allele rs8113308	1.27 (1.02–1.59)	3.61 × 10⁻²
Endocrine	0.59 (0.44–0.80)	6.76 × 10⁻⁴
PR	0.60 (0.46–0.78)	1.68 × 10⁻⁴
T	1.45 (1.27–1.67)	8.89 × 10⁻⁸
N	2.14 (1.61–2.85)	1.92 × 10⁻⁷
M	1.60 (1.02–2.51)	3.91 × 10⁻²
Grade	1.52 (1.25–1.84)	2.32 × 10⁻⁵
Per allele model including per allele SNP:endocrine interaction term
Covariate	HR (95% CI)	P
Per-allele rs8113308	0.75 (0.49–1.17)	2.06 × 10⁻¹
Endocrine	0.22 (0.11–0.45)	2.65 × 10⁻⁵
PR	0.58 (0.45–0.76)	6.80 × 10⁻⁵
T	1.44 (1.25–1.65)	2.47 × 10⁻⁷
N	2.12 (1.59–2.82)	2.76 × 10⁻⁷
M	1.62 (1.04–2.54)	3.40 × 10⁻²
Grade	1.52 (1.25–1.85)	2.31 × 10⁻⁵
Per-allele rs8113308:Endocrine	2.16 (1.30–3.60)	3.13 × 10⁻³
Likelihood ratio test P value	0.0021
Codominant model assuming no interaction
Covariate	HR (95% CI)	P
rs8113308 A/G	1.22 (0.93–1.60)	1.49 × 10⁻¹
rs8113308 G/G	1.87 (0.96–3.66)	6.79 × 10⁻²
Endocrine	0.56 (0.44–0.80)	6.56 × 10⁻⁴
PR	0.60 (0.46–0.78)	1.66 × 10⁻⁴
T	1.46 (1.27–1.67)	8.13 × 10⁻⁸
N	2.13 (1.60–2.84)	2.25 × 10⁻⁷
M	1.60 (1.02–2.50)	4.06 × 10⁻²
Grade	1.52 (1.25–1.84)	2.31 × 10⁻⁵
Codominant model including per genotype SNP:endocrine interaction term
Covariate	HR (95% CI)	P
rs8113308 A/G	0.79 (0.48–1.28)	3.34 × 10⁻¹
rs8113308 G/G	0.41 (0.06–2.98)	3.78 × 10⁻¹
Endocrine	0.49 (0.35–0.68)	1.93 × 10⁻⁵
PR	0.58 (0.44–0.76)	6.27 × 10⁻⁵
T	1.43 (1.25–1.65)	3.80 × 10⁻⁷
N	2.12 (1.59–2.82)	2.82 × 10⁻⁷
M	1.65 (1.05–2.59)	2.94 × 10⁻²
Grade	1.52 (1.25–1.84)	2.37 × 10⁻⁵
rs8113308A/G:Endocrine	1.95 (1.08–3.49)	2.58 × 10⁻²
rs8113308G/G:Endocrine	7.77 (0.93–64.71)	5.79 × 10⁻²
Likelihood ratio test P value	0.0078

NOTE: The model was stratified by study and adjusted by age and used 10-year breast cancer–specific survival and included ER-positive cases only; per allele model assuming no interaction and per allele model including per allele SNP:endocrine interaction term. Likelihood ratio test P = 0.0021. Codominant model assuming no interaction and codominant model including per genotype SNP:endocrine interaction term. Likelihood ratio test P = 0.0078.

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Supplementary Data

Supplementary Methods and Supplementary Tables S1-S6 - Supplementary Methods and Supplementary Tables S1-S6. Supplementary Table S1. Univariate Cox's regression analysis within estrogen receptor positive patients receiving endocrine treatment with stage-1 meta-analysis fullfilling the P-value thresholds. Supplementary Table S2. Association for SNP rs8113308 with clinical and pathological features of the breast cancer tumors in a pooled set of HEBCS GWS, POSH GWS and POSH validation. Supplementary Table S3. Association for SNP rs4767413 with clinical and pathological features of the breast cancer tumors in a pooled set of HEBCS GWS, POSH GWS and POSH validation. Supplementary Table S4. Cis eQTL analysis. Expression in ER positive breast tumor and in ER negative breast tumor from METABRIC. Supplementary Table S5. Peripheral blood eQTL. Supplementary Table S6. Trans eQTL analysis. Expression in ER positive breast tumor and in ER negative breast tumor from METABRIC.
Supplementary Figure S1 - Supplementary Figure S1. REMARK diagram describing work flow and sample selection in this study.
Supplementary Figure S2 - Supplementary Figure S2. Kaplan-Meier plots of cumulative breast cancer specific 10-year survival of rs8113308 genotypes in HEBCS GWS
Supplementary Figure S3 - Supplementary Figure S3. Kaplan-Meier plots of cumulative 10-year survival of rs8113308 genotypes in POSH validation dataset
Supplementary Figure S4 - Supplementary Figure S4. Forest plots of hazard ratios and their confidence intervals separately for studies HEBCS GWS and POSH GWS (stage-1) and POSH validation and SUCCESS-A (stage-2) along with the meta-analysis P-value of the stage-1 and stage-2.
Supplementary Figure S5 - Supplementary Figure S5. Regional plot using P-values derived from univariate Cox's regression model from HEBCS and POSH GWS meta-analysis and includes both imputed and the genotyped SNPs 250 kb either side of the rs8113308.
Supplementary Figure S6 - Supplementary Figure S6. Protein-protein interaction network.
Legends to Supplementary Figures S1 to S6 - Legends to Supplementary Figures S1 to S6. This document comprises the legends to the supplementary figures.