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Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.

Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PP, Seibold P, Fasching PA, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, García-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann MW, Knight JA, Glendon G, Tchatchou S, Alnæs GI, Borresen-Dale AL, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer HU, Rüdiger T, Jager A, van Deurzen CH, Tilanus-Linthorst MM, Muranen TA, Aittomäki K, Blomqvist C, Margolin S, Kosma VM, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips KA, kConFab InvestigatorsLinn S, Cornelissen S, van den Broek SA, Kang D, Choi JY, Park SK, Yoo KY, Hsiung CN, Wu PE, Hou MF, Shen CY, Teo SH, Taib NA, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J - Breast Cancer Res. (2015)

Bottom Line: Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized.Similar associations were observed with BCSS.Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).

Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.

Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻⁴) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻⁴), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻⁴). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity.

Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

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Kaplan-Meier survival curves of overall survival in estrogen receptor (ER)-negative patients who had chemotherapy forTGFBR2rs1367610. The survival curves for TGFBR2 rs1367610 (G > C) stratified by genotype are shown for the Breast Cancer Association Consortium European sample. The P-value of the log-rank test was 2.0 × 10−4. The number of events and cases in parenthesis for each genotype are GG (180/1139, blue line), GC (80/338, green line) and CC (7/22, red line) respectively.
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Fig3: Kaplan-Meier survival curves of overall survival in estrogen receptor (ER)-negative patients who had chemotherapy forTGFBR2rs1367610. The survival curves for TGFBR2 rs1367610 (G > C) stratified by genotype are shown for the Breast Cancer Association Consortium European sample. The P-value of the log-rank test was 2.0 × 10−4. The number of events and cases in parenthesis for each genotype are GG (180/1139, blue line), GC (80/338, green line) and CC (7/22, red line) respectively.

Mentions: In TGFBR2, the strongest association in ER-negative patients who received chemotherapy was seen for SNP rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22, 1.95), P = 3.08 × 10−4). A regional association plot for all SNPs in TGFBR2 is shown in Figure 2. The Kaplan-Meier survival curve stratified by genotype of SNP rs1367610 is shown in Figure 3. For the univariate survival curves, the P-value of the log-rank test was 2.0 × 10−4. There was no evidence of heterogeneity for the association across eight studies with at least ten events in ER-negative patients with chemotherapy (Additional file 1: Figure S2). This SNP was not associated with OS in ER-negative patients who did not receive chemotherapy (P-value for interaction = 8.82 × 10−4) or with ER-positive patients who received chemotherapy (P-value for interaction = 2.62 × 10−4). Variant alleles of nine further SNPs in TGFBR2 in strong LD with rs1367610 (r2 ≥ 0.97) were similarly associated with poorer OS in ER-negative breast cancer patients treated with chemotherapy (Additional file 2: Table S3). After accounting for rs1367610, none of other nine TGFBR2 variants showed association with OS.Figure 2


Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.

Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PP, Seibold P, Fasching PA, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, García-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann MW, Knight JA, Glendon G, Tchatchou S, Alnæs GI, Borresen-Dale AL, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer HU, Rüdiger T, Jager A, van Deurzen CH, Tilanus-Linthorst MM, Muranen TA, Aittomäki K, Blomqvist C, Margolin S, Kosma VM, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips KA, kConFab InvestigatorsLinn S, Cornelissen S, van den Broek SA, Kang D, Choi JY, Park SK, Yoo KY, Hsiung CN, Wu PE, Hou MF, Shen CY, Teo SH, Taib NA, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J - Breast Cancer Res. (2015)

Kaplan-Meier survival curves of overall survival in estrogen receptor (ER)-negative patients who had chemotherapy forTGFBR2rs1367610. The survival curves for TGFBR2 rs1367610 (G > C) stratified by genotype are shown for the Breast Cancer Association Consortium European sample. The P-value of the log-rank test was 2.0 × 10−4. The number of events and cases in parenthesis for each genotype are GG (180/1139, blue line), GC (80/338, green line) and CC (7/22, red line) respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4374346&req=5

Fig3: Kaplan-Meier survival curves of overall survival in estrogen receptor (ER)-negative patients who had chemotherapy forTGFBR2rs1367610. The survival curves for TGFBR2 rs1367610 (G > C) stratified by genotype are shown for the Breast Cancer Association Consortium European sample. The P-value of the log-rank test was 2.0 × 10−4. The number of events and cases in parenthesis for each genotype are GG (180/1139, blue line), GC (80/338, green line) and CC (7/22, red line) respectively.
Mentions: In TGFBR2, the strongest association in ER-negative patients who received chemotherapy was seen for SNP rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22, 1.95), P = 3.08 × 10−4). A regional association plot for all SNPs in TGFBR2 is shown in Figure 2. The Kaplan-Meier survival curve stratified by genotype of SNP rs1367610 is shown in Figure 3. For the univariate survival curves, the P-value of the log-rank test was 2.0 × 10−4. There was no evidence of heterogeneity for the association across eight studies with at least ten events in ER-negative patients with chemotherapy (Additional file 1: Figure S2). This SNP was not associated with OS in ER-negative patients who did not receive chemotherapy (P-value for interaction = 8.82 × 10−4) or with ER-positive patients who received chemotherapy (P-value for interaction = 2.62 × 10−4). Variant alleles of nine further SNPs in TGFBR2 in strong LD with rs1367610 (r2 ≥ 0.97) were similarly associated with poorer OS in ER-negative breast cancer patients treated with chemotherapy (Additional file 2: Table S3). After accounting for rs1367610, none of other nine TGFBR2 variants showed association with OS.Figure 2

Bottom Line: Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized.Similar associations were observed with BCSS.Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).

Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.

Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻⁴) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻⁴), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻⁴). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity.

Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

Show MeSH
Related in: MedlinePlus