PO.PS01.05 · 人群科学

非洲血统、Duffy-null 基因型与一组黑人女性队列中的上皮性卵巢癌

African ancestry, Duffy-null genotype, and epithelial ovarian cancer in a cohort of Black women

编号 2340 展板 6 时间 4/20 09:00–12:00 区域 Section 36 主讲 Joellen Schildkraut, BS;MPH;PhD

分会场 Epidemiology: Cancer Incidence, Mortality, Patterns, and Methodology

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作者与单位 Authors & Affiliations

Joellen M. Schildkraut¹, Jeffrey R. Marks², Xintian Song³, Yao Xin⁴, Anthony J. Alberg⁵, Lauren C. Peres⁶, Katherine Anne Lawson-Michod⁷, Lindsay Jane Collin⁸, Jennifer A. Doherty⁹, Andrew B. Lawson¹⁰, on behalf of the African American Cancer Epidemiology Study

¹Emory University, Rollins School of Public Health, Atlanta, GA,²Surgery, Duke University, Durham, NC,³Epidemiology, Emory University, Rollins School of Public Health, Atlanta, GA,⁴Medical College of South Carolina, Charleston, SC,⁵Epidemiology, University of South Carolina, Columbia, SC,⁶Moffitt Cancer Institute, Tampa, FL,⁷Fred Hutchinson Cancer Center, Seattle, WA,⁸Emory University, Rollins School of Public Health, Salt Lake City, UT,⁹University of Utah Huntsman Cancer Institute, Salt Lake City, UT,¹⁰Biostatistics, Medical College of South Carolina, Charleston, SC

摘要 Abstract

中文摘要

背景：黑人女性罹患上皮性卵巢癌（EOC）后生存状况较差，这在所有诊断分期及各 EOC 组织学亚型中均是如此。我们呈现了在一组黑人/非裔美国女性队列中，非洲血统及非典型趋化因子受体 1（ACKR1）基因中一个与血统相关的基因型对 EOC 生存影响的研究结果。我们还报告了其与肿瘤分子特征的关联，这些特征可能解释与 Duffy-null ACKR1 基因型相关的潜在生物学机制。方法：在一组参与了基于人群的非裔美国人癌症流行病学研究（AACES）的 408 名患有 EOC（其中 275 名为高级别浆液性卵巢癌（HGSC））的黑人女性队列中，采用贝叶斯建模方法，在校正分期、诊断年龄、社会经济地位的 Yost 指数、教育程度和卵巢癌家族史后，确定全基因组非洲血统及 ACKR1 基因启动子区域 rs2814778 SNP 与生存之间的关系。全基因组非洲血统比例及 ACKR1 基因型（Duffy-null（CC）vs. TC/TT）由种系 DNA 确定。肿瘤分子特征包括采用 RNAseq 测定的基因表达、采用多重免疫荧光（mIF）测定的肿瘤免疫（即 T 细胞丰度），以及由全外显子组测序数据得出的同源重组缺陷（HRD），均来自 HGSC 肿瘤。结果：在所有 EOC 病例中，Duffy-null 基因型出现于 70.6% 的病例，在 HGSC 中占 72.0%。其患病率在高非洲血统者（非洲血统 >83.6%）中高于低非洲血统者（分别为 83.2% 和 58.3%）。Duffy-null 基因型与 EOC 病例生存改善相关（校正风险比（HR）=0.59，95% 可信区间（CI）：0.35-0.96）。HGSC 对应的 HR 为 0.61（95% CI：0.34-1.12）。然而，全基因组非洲血统——以 logit 尺度上非洲血统百分比每增加 1% 表示——提示与较差的生存相关，尤其是对 HGSC，其 HR 为 1.31（95% CI：0.89-1.90）。此外，我们检验了 HGSC 中 CC vs. TC/TT 基因型与肿瘤分子特征之间的关系。Duffy-null 基因型与较低的 ACKR1 表达、较低的细胞毒性 T 细胞丰度以及 HGSC 中较高的 HRD 相关。在 EOC 受试者中，mIF 检测的髓系细胞（CD11b+）在高非洲血统者中丰度较低，这与较差的生存相一致。结论：Duffy-null 基因型与黑人女性 EOC 死亡率降低约 40% 相关。较低的 T 细胞浸润可能反映较低的免疫监视，并可能与 Duffy-null 个体 HGSC 中较高的 HRD 相伴发生。尤其是 HRD 这一发现，可能解释了 Duffy-null 基因型所观察到的预后改善，因为我们团队此前已表明，HRD 状态与黑人 HGSC 女性更好的生存相关。

查看英文原文 English abstract

Background: Black women experience poor survival from epithelial ovarian cancer (EOC), for all stages at diagnosis and EOC histotypes. We present findings of the contribution of African ancestry and an ancestry-related genotype in the Atypical Chemokine Receptor 1 ( ACKR1 ) gene to EOC survival among a cohort of Black/African American women. We also report associations with tumor molecular features that may explain the potential underlying biology related to the Duffy-null ACKR1 genotypes. Methods: The relationship between global African ancestry and the rs2814778 SNP in the promotor region of the ACKR1 gene and survival was determined in a cohort of 408 Black women with EOC (275 with high grade serous ovarian cancer (HGSC)) who participated in the population-based African American Cancer Epidemiology Study (AACES) using a Bayesian modeling approach adjusting for stage, age at diagnosis, the Yost index for socioeconomic status, education, and ovarian cancer family history. Proportion of global African ancestry and the ACKR1 genotype (Duffy-null (CC) vs. TC/ TT) were determined from germline DNA. Tumor molecular features including gene expression using RNAseq, tumor immunity (i.e., T-cell abundance) measured using multiplex immunofluorescence (mIF), and homologous recombination deficiency (HRD) derived from whole exome sequencing data were generated from HGSC tumors. Results: The Duffy-null genotype was present in 70.6% EOC cases overall, and 72.0% of HGSC. The prevalence was higher among individuals with high African ancestry (African ancestry >83.6%) than those with lower African ancestry (83.2% and 58.3%, respectively). The Duffy-null genotype was associated with improved survival among EOC cases (adjusted Hazard Ratio (HR)=0.59, 95% credible intervals (CI): 0.35-0.96). The corresponding HR for HGSC was 0.61 (95% CI: 0.34-1.12). However, global African ancestry-as indicated by a 1% increase in percent African ancestry on the logit scale-was suggestively associated with worse survival, especially for HGSC, with an HR of 1.31 (95% CI: 0.89-1.90). Additionally, we examined the relationship between the CC vs. TC/ TT genotypes and tumor molecular features in HGSC. The Duffy-null genotype was associated with lower ACKR1 expression, lower cytotoxic T cell abundance, and higher HRD in HGSC. Among EOC subjects, mIF-derived myeloid cells (CD11b+) showed lower abundance in those with high African ancestry, which is consistent with worse survival. Conclusion: The Duffy-null genotype is associated with ~40% decreased EOC mortality in Black women. Lower T-cell infiltrates may reflect lower immune surveillance and may coincide with higher HRD in HGSC among Duffy-null individuals. The HRD finding, in particular, may explain the improved prognosis observed with the Duffy-null genotype, as our group has previously shown that HRD status was associated with better survival in Black women with HGSC.

利益披露 Disclosure

J. M. Schildkraut, None.. J. R. Marks, None.. X. Song, None.. Y. Xin, None.. A. J. Alberg, None.. L. C. Peres, None.. A. B. Lawson, None.

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