背景:原发性乳腺癌的转移在转移性疾病诊断时可能涉及单个或多个器官。临床人群中特定转移扩散模式的分子风险因素是有限的。
方法:使用包括1357例原发性乳腺癌的病例对照设计来研究三种不同的临床转移模式,发生在转移性疾病的前六个月内:骨骼和内脏间异步传播,只有骨头,和仅内脏转移。使用全基因组(WG)-DASL测定从福尔马林固定的石蜡包埋(FFPE)样品获得全基因组表达谱。开发了用于处理FFPE样品以及严格的数据质量控制的系统方案,以鉴定稳健的表达谱数据。测试了一组已发表和新颖的基因集与这些特定的转移扩散模式的关联,并计算了比值比(OR)。
结果:在所有固有的乳腺癌亚型中都发现了向骨和内脏的亚同步转移,而免疫组织化学(IHC)定义的受体状态和特定的IntClust亚组是仅内脏或仅骨性首次转移的危险因素。在基因模块中,与增殖相关的因素增加了间异步转移(OR(95%CI)=2.3(1.1~4.8))和仅内脏首次转移(OR(95%CI)=2.5(1.2~5.1))的风险,但不增加仅骨转移(OR(95%CI)=0.97(0.56~1.7))的风险.在雌激素受体阳性乳腺癌中鉴定出21基因模块(BV),并向骨骼和内脏转移(曲线下面积=0.77),它的表达增加了该人群中骨和内脏非同步传播的风险。BV在原发性乳腺癌中进一步用NanoStringnCounter正交验证,并且在匹配的淋巴结转移和外部队列中可重复。
结论:这项来自FFPE肿瘤样本的WG-DASL整体表达谱的病例对照研究,经过仔细的质量控制和RNA选择,揭示了原发肿瘤中的基因模块对于亚异步第一转移的临床模式具有不同的风险。此外,一个新的基因模块被认为是骨和内脏首次转移扩散的假定危险因素,对疾病监测和治疗计划有潜在影响。
BACKGROUND: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.
METHODS: A
case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.
RESULTS: Metasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1-4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2-5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56-1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.
CONCLUSIONS: This
case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.