Wen Wei Xiong, Soo Jaslyn Sian-Siu, Kwan Pui Yoke, Hong Elaine, Khang Tsung Fei, Mariapun Shivaani, Lee Christine Shu-Mei, Hasan Siti Norhidayu, Rajadurai Pathmanathan, Yip Cheng Har, Mohd Taib Nur Aishah, Teo Soo Hwang
Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
Breast Cancer Research Unit, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
Breast Cancer Res. 2016 May 27;18(1):56. doi: 10.1186/s13058-016-0717-1.
APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system.
In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT.
The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values < 0.05). Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells (P < 0.001).
Taken together, our data suggests that tumour-infiltrating immune cells may be an important feature of breast cancers arising in women with APOBEC3B germline deletion, and that this may be of particular interest in Asian women where the germline deletion is more common.
载脂蛋白B mRNA编辑酶催化多肽样3B（APOBEC3B）是一种胞嘧啶脱氨酶，与病毒感染的免疫反应、癌症易感性和致癌作用有关。种系APOBEC3B缺失在东亚女性中更为常见，在东亚和白种女性中均赋予乳腺癌适度风险。对欧洲血统女性的肿瘤样本分析表明，种系APOBEC3B缺失与发生体细胞突变的倾向增加以及免疫反应相关基因集的富集有关。然而，在亚洲肿瘤样本中尚未对此进行研究，因为亚洲人群在遗传和饮食因素方面的差异可能会对免疫系统产生影响。
在本研究中，我们在一个基于医院的亚洲多民族队列中确定了种系APOBEC3B缺失的患病率及其与乳腺癌风险的关联，该队列包括来自马来西亚的1451例病例和1442例对照。我们使用微阵列分析比较了APOBEC3B缺失携带者和非携带者所患乳腺癌的基因表达谱。最后，我们使用ESTIMATE对来自癌症基因组图谱（TCGA）和乳腺浸润性癌分子分类国际联盟（METABRIC）的乳腺癌中肿瘤浸润免疫细胞的总体丰度进行了表征，并使用CIBERSORT对来自METABRIC的乳腺癌中22个免疫细胞亚群的相对频率进行了表征。
估计在中国、马来和印度裔女性人群中，APOBEC3B缺失的次要等位基因频率分别为0.35、0.42和0.16，并且种系APOBEC3B缺失与乳腺癌风险相关，与无缺失的女性相比，单拷贝缺失的比值比为1.23（95%置信区间：[1.05，1.44]），双拷贝缺失的比值比为1.38（95%置信区间：[1.10，1.74]）。种系APOBEC3B缺失与任何临床病理特征或任何APOBEC家族成员的表达均无关联，但与免疫反应相关基因集有关（错误发现率q值<0.05）。对来自METABRIC的乳腺癌分析显示，APOBEC3B缺失携带者的乳腺癌中肿瘤浸润免疫细胞的丰度显著更高（P<0.001）。
综上所述，我们的数据表明，肿瘤浸润免疫细胞可能是种系APOBEC3B缺失女性所患乳腺癌的一个重要特征，并且这在种系缺失更为常见的亚洲女性中可能特别值得关注。
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