Format

Send to

Choose Destination
Breast Cancer Res. 2017 Oct 13;19(1):113. doi: 10.1186/s13058-017-0881-y.

Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study.

Author information

1
School of Cancer Studies, CRUK King's Health Partners Centre, King's College London, Guy's Campus, London, SE1 1UL, UK.
2
Institute for Mathematical and Molecular Biomedicine, King's College London, Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
3
NIHR Comprehensive Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, London, WC2R 2LS, UK.
4
Research Oncology, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, SE1 9RT, UK.
5
Cancer Epidemiology Unit, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
6
Cancer Bioinformatics, King's College London, Innovation Centre, Cancer Centre at Guy's Hospital, London, SE1 9RT, UK.
7
Breast Cancer Now Research Unit, Innovation Centre, Cancer Centre at Guy's Hospital, King's Health Partners AHSC, King's College London, Faculty of Life Sciences and Medicine, London, SE1 9RT, UK.
8
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
9
CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
10
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of Beijing, Beijing, People's Republic of China, Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, People's Republic of China.
11
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
12
Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Campus, London, SE1 1UL, UK.
13
UCL Cancer Institute, Paul O'Gorman Building, University College London, London, WC1E 6DD, UK.
14
London Research Institute, Lincoln's Inn Fields, London, WC2A 3LY, UK.
15
Uppsala University, Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden.
16
School of Cancer Studies, CRUK King's Health Partners Centre, King's College London, Guy's Campus, London, SE1 1UL, UK. anita.grigoriadis@kcl.ac.uk.
17
Research Oncology, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, SE1 9RT, UK. anita.grigoriadis@kcl.ac.uk.
18
Cancer Bioinformatics, King's College London, Innovation Centre, Cancer Centre at Guy's Hospital, London, SE1 9RT, UK. anita.grigoriadis@kcl.ac.uk.
19
Breast Cancer Now Research Unit, Innovation Centre, Cancer Centre at Guy's Hospital, King's Health Partners AHSC, King's College London, Faculty of Life Sciences and Medicine, London, SE1 9RT, UK. anita.grigoriadis@kcl.ac.uk.
20
School of Cancer Studies, CRUK King's Health Partners Centre, King's College London, Guy's Campus, London, SE1 1UL, UK. EA-Purushotham@kcl.ac.uk.
21
Research Oncology, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, SE1 9RT, UK. EA-Purushotham@kcl.ac.uk.

Abstract

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.

KEYWORDS:

Breast cancer; Gene expression pattern; Metasynchronous metastases

PMID:
29029636
PMCID:
PMC5640935
DOI:
10.1186/s13058-017-0881-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center