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Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study
Kings Coll London, Sch Canc Studies, CRUK Kings Hlth Partners Ctr, Guys Campus, London SE1 1UL, England.;Kings Coll London, Ins Math & Mol Biomed, Hodgkin Bldg,Guys Campus, London SE1 1UL, England..
Guys & St Thomas NHS Fdn Trust, NIHR Comprehens Biomed Res Ctr, London WC2R 2LS, England.;Kings Coll London, London WC2R 2LS, England..
Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England..
Kings Coll London, Guys Hosp, Res Oncol, Fac Life Sci & Med, London SE1 9RT, England.;Kings Coll London, Guys Hosp, Canc Epidemiol Unit, London SE1 9RT, England..
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2017 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 19, article id 113Article in journal (Refereed) Published
Abstract [en]

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.

Conclusion: 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.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD , 2017. Vol. 19, article id 113
Keywords [en]
Breast cancer, Metasynchronous metastases, Gene expression pattern
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-337331DOI: 10.1186/s13058-017-0881-yISI: 000412892700001PubMedID: 29029636OAI: oai:DiVA.org:uu-337331DiVA, id: diva2:1170483
Funder
EU, FP7, Seventh Framework Programme, 259881Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-01-03Bibliographically approved

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