Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.
Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy.
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DOI：
10.1158/1078-0432.ccr-15-0296
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发表时间：
2015-09-15
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影响因子：
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通讯作者：
Nevanlinna H
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作者：
Khan S;Fagerholm R;Rafiq S;Tapper W;Aittomäki K;Liu J;Blomqvist C;Eccles D;Nevanlinna H
尽管大多数雌激素受体（ER）阳性乳腺癌患者从内分泌治疗中受益，但也有相当一部分患者没有受益。我们的目的是确定可能预测接受辅助内分泌治疗的患者的生存率的遗传性遗传变异。我们对两项全基因组研究进行了荟萃分析；赫尔辛基乳腺癌研究，805 名患者，其中 240 名接受内分泌治疗，以及散发性与遗传性乳腺癌结果的前瞻性研究，536 名患者，其中 155 名接受内分泌治疗的患者，评估了 486,478 个单核苷酸多态性 (SNP)。在总共 5011 名患者的两个独立数据集中进一步研究了内分泌治疗亚组的前 4 个关联，其中 3485 名患者接受内分泌治疗。一项荟萃分析发现了一个常见的 SNP rs8113308，映射到 19q13.41，与内分泌治疗患者的生存率降低相关（风险比 (HR) 1.69，95% 置信区间 (CI) 1.37-2.07，P = 6.34 ×10−7），并提高 ER 阴性患者的生存率，在未接受内分泌治疗的 ER 阳性病例中也有类似的趋势。在针对传统预后因素进行调整的多变量分析中，我们发现 rs8113308 与内分泌治疗之间存在显着的相互作用，表明 SNP rs8113308 对乳腺癌生存具有预测性、治疗特异性效应，相互作用的每个等位基因 HR 为 2.16（95% CI 1.30 – 3.60，Pinteraction = 0.003），HR=7.77（95% CI 0.93 – 64.71）对于纯合基因型携带者。计算机功能分析提出了生物学原理。我们的研究结果表明，携带 rs8113308 罕见等位基因可能会识别出无法从辅助内分泌治疗中受益的患者。
Although most estrogen receptor (ER)-positive breast cancer patients benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies. We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy-patients, evaluating 486,478 single nucleotide polymorphisms (SNPs). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totalling 5011 patients, with 3485 receiving endocrine therapy. A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine treated patients (hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.37-2.07, P = 6.34 ×10−7) and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI 1.30 – 3.60, Pinteraction = 0.003) and HR=7.77 (95% CI 0.93 – 64.71) for the homozygous genotype carriers. A biological rationale is suggested by in silico functional analyses. Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.