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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

Lawler, Katherine; Papouli, Efterpi; Naceur-Lombardelli, Cristina; Mera, Anca; Ougham, Kayleigh; Tutt, Andrew; Kimbung, Siker LU ; Hedenfalk, Ingrid LU ; Zhan, Jun and Zhang, Hongquan, et al. (2017) In Breast Cancer Research 19(1).
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... (More)

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.

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publication status
published
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keywords
Breast cancer, Gene expression pattern, Metasynchronous metastases
in
Breast Cancer Research
volume
19
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85031034493
  • wos:000412892700001
ISSN
1465-5411
DOI
10.1186/s13058-017-0881-y
language
English
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yes
id
95e5fb1d-668c-40e4-8b2e-75c51157ff5b
date added to LUP
2017-11-02 10:02:12
date last changed
2018-01-16 13:25:13
@article{95e5fb1d-668c-40e4-8b2e-75c51157ff5b,
  abstract     = {<p>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.</p>},
  articleno    = {113},
  author       = {Lawler, Katherine and Papouli, Efterpi and Naceur-Lombardelli, Cristina and Mera, Anca and Ougham, Kayleigh and Tutt, Andrew and Kimbung, Siker and Hedenfalk, Ingrid and Zhan, Jun and Zhang, Hongquan and Buus, Richard and Dowsett, Mitch and Ng, Tony and Pinder, Sarah E and Parker, Peter and Holmberg, Lars and Gillett, Cheryl E. and Grigoriadis, Anita and Purushotham, Arnie},
  issn         = {1465-5411},
  keyword      = {Breast cancer,Gene expression pattern,Metasynchronous metastases},
  language     = {eng},
  month        = {10},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Breast Cancer Research},
  title        = {Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread : A case control study},
  url          = {http://dx.doi.org/10.1186/s13058-017-0881-y},
  volume       = {19},
  year         = {2017},
}