School of Cancer Studies, CRUK King's Health Partners Centre, King's College London, Guy's Campus, London, SE1 1UL, UK.
Institute for Mathematical and Molecular Biomedicine, King's College London, Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
Breast Cancer Res. 2017 Oct 13;19(1):113. doi: 10.1186/s13058-017-0881-y.
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.
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.
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.
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.
原发性乳腺癌转移可在转移疾病诊断时累及单一或多个器官。对于临床人群中特定转移扩散模式的分子危险因素有限。
采用病例对照设计，纳入 1357 例原发性乳腺癌，研究三种不同的转移临床模式，这些模式发生在转移疾病的前六个月内：骨和内脏转移同步扩散、仅骨转移和仅内脏转移。使用福尔马林固定石蜡包埋（FFPE）样本中的全基因组（WG）-DASL 检测获得全基因组表达谱。制定了一个系统方案来处理 FFPE 样本，并进行严格的数据质量控制，以识别稳健的表达谱数据。测试了一组已发表和新的基因集，以确定它们与这些特定转移扩散模式的关联，并计算比值比（OR）。
在所有内在乳腺癌亚型中均发现骨和内脏转移同步发生，而免疫组织化学（IHC）定义的受体状态和特定 IntClust 亚组是仅内脏或仅骨首次转移的危险因素。在基因模块中，与增殖相关的基因模块增加了转移同步（OR（95%CI）=2.3（1.1-4.8））和仅内脏转移的风险（OR（95%CI）=2.5（1.2-5.1）），但不增加仅骨转移的风险（OR（95%CI）=0.97（0.56-1.7））。在雌激素受体阳性乳腺癌中鉴定出与骨和内脏转移同步的 21 个基因模块（BV）（曲线下面积=0.77），其表达增加了该人群中骨和内脏转移同步的风险。在原发性乳腺癌中，BV 进一步与 NanoString nCounter 正交验证，并在其匹配的淋巴结转移和外部队列中具有重现性。
这项病例对照研究使用 FFPE 肿瘤样本中的 WG-DASL 全基因组表达谱，经过仔细的质量控制和 RNA 选择，揭示了原发性肿瘤中的基因模块具有不同的临床模式，即同步首次转移的风险。此外，鉴定出一个新的基因模块作为潜在的同步骨和内脏首次转移的危险因素，这可能对疾病监测和治疗计划有影响。
