Identification and prioritization of candidate genes for symptom variability in breast cancer survivors based on disease characteristics at the cellular level

Figures & data

Figure 1 Conceptual model of using variability in genes evaluated as part of prognostic multigene expression profiles for breast cancer to test the hypothesis that heterogeneity in the biology of breast cancers at the cellular level could account for symptom variation.

Note: Dashed arrows represent relationships to be tested in future investigations.

Table 1 Prognostic multigene expression profiles

Profile	Provider	Number of cancer genes evaluated	Clinical utility	Patient eligibility	Website	Reference
11-gene expression signature	Breast Cancer Index^SM bioTheranostics, Inc. (San Diego, CA, USA)	7 (5 gene molecular grade index; 2 gene HOXB13: IL17BR index, an expression ratio biomarker)	Predicts late (5–10 year) and overall (0–10 year) recurrence risk as well as likelihood of endocrine therapy benefit; stratifies patients into high or low risk of distant recurrence and high or low likelihood of benefit from extended endocrine therapy	Patients with ER (+), lymph node (−/+, 1–3 positive nodes), early stage breast cancer who are distant recurrence-free	http://breastcancerindex.com	^Citation20^–^Citation22
14-gene prognostic expression signature	Not currently supported	14	Predicts distant metastasis; guides treatment decisions related to adjuvant therapy	Patients with ER (+),lymph node (−), early stage breast cancer	NA	^Citation23
21-gene breast cancer assay	Oncotype DX^® Genomic Health^®, Inc. (Redwood City, CA, USA)	16 (for invasive breast cancer) 7 (for DCIS)	Predicts 10-year risk of distant recurrence and likelihood of chemotherapy benefit for invasive breast cancer; gene expression levels are aggregated and provided as a scaled Recurrence Score^® result (on a 0–100 scale); patients are stratified into high, intermediate, or low risk groups; also provides quantitative single gene scores for ER, PR, and HER2; predicts 10-year risk of distant recurrence (DCIS or invasive) for DCIS	Pre- or post-menopausal patients with ER (+), lymph node (−), HER2 (−),stage I, II or IIIa invasive breast cancer Post-menopausal patients with lymph node (+, 1–3 positive nodes), HR (+),HER2 (−), stage I, II or IIIa invasive breast cancer DCIS treated by lumpectomy, not mastectomy, regardless of Tamoxifen status (+/−)	http://breast-cancer.oncotypedx.com	^Citation24,Citation25
50-gene breast cancer prognostic gene signature assay	Prosigna^® NanoString^® Technologies, Inc. (Seattle, WA, USA)	50	Predicts 10-year distant recurrence-free survival using gene-algorithm generated Prosigna^® Score (0–100); stratifies patients into high, intermediate, or low risk groups. Provides risk group classification to facilitate interpretation of Prosigna^® score with clinical outcomes	Post-menopausal patients with HR (+),lymph node (−), stage I or II invasive breast cancer to be treated with adjuvant endocrine therapy alone Post-menopausal patients with HR (+),lymph node (+, 1–3 positive nodes), stage II invasive breast cancer treated with adjuvant endocrine therapy alone	http://www.prosigna.com	^Citation26
70-gene breast cancer recurrence assay	MammaPrint^® Agendia^® (Irvine, CA, USA)	70	Predicts 5- and 10-year distant recurrence and guides treatment decisions, including potential chemotherapy benefit; stratifies patients into low or high risk groups	Patients with ER (+/−), lymph node (−),stage I or II invasive breast cancer tumor ≤5 cm in size	http://www.agendia.com/healthcare-professionals/breast-cancer/mammaprint	^Citation27

Notes: Information regarding Prosigna^® is provided courtesy of NanoString Technologies, Inc., www.Prosigna.com. © 2014–15 NanoString Technologies, Inc. All rights reserved. Information regarding Oncotype DX^® is provided courtesy of Genomic Health, Inc., www.genomichealth.com. © 2015 Genomic Health, Inc., All rights reserved.

Abbreviations: DCIS, ductal carcinoma in situ; ER, estrogen receptor; HR, hormone receptor; PR, progesterone receptor.

Figure 2 Overlapping canonical pathways map representing shared biology among the identified candidate genes.

Notes: Connected canonical pathways share one or more genes in common. The brighter the red of the node, the more significant the canonical pathway in the gene set. The canonical pathways map was generated through the use of QIAGEN’s Ingenuity Pathway Analysis (IPA^®, QIAGEN Redwood City, www.qiagen.com/ingenuity).

Figure 3 Gene–gene networks generated by pathway analysis.

Notes: The networks were generated through the use of QIAGEN’s Ingenuity Pathway Analysis (IPA^®, QIAGEN Redwood City, www.qiagen.com/ingenuity). Identified candidate genes are highlighted in green. All identified candidate genes are included. The main associated functions of each network are as follows: (A) cancer, organismal injury and abnormalities, and reproductive system disease; (B) DNA replication, recombination, and repair, connective tissue disorders, and dental disease; and (C) cellular development, reproductive system development and function, and molecular transport. The node shapes and relationship type legend can be found at http://ingenuity.force.com/ipa/articles/Feature_Description/Legend.

Table 2 Genes utilized in two or more prognostic multigene expression profiles as indicated by X

Gene	11-gene expression profile	14-gene prognostic expression signature	21-gene breast cancer assay	50-gene breast cancer prognostic gene signature assay	70-gene breast cancer recurrence assay	Gene function
BAG1			X	X		Enhances antiapoptotic effect of BCL2
BCL2			X	X		Blocks the apoptotic death of certain cells
BIRC5			X	X		Encodes regulatory proteins that prevent apoptosis
CCNB1a		X	X	X		Encodes a regulatory protein involved in mitosis
CENPAa	X	X			X	Encodes for a centromere protein; histone H3 variant
CMC2		X			X	Potential involvement in mitochondrial cytochrome c oxidase biogenesis^Citation34
DIAPH3		X			X	Involved in actin remodeling and regulation of cell movement and adhesion
ERBB2			X	X		Encodes HER2, an epidermal growth factor receptor protein
ESR1			X	X		Encodes an estrogen receptor
GRB7			X	X		Encodes a growth factor receptor-binding protein
MELKa		X		X	X	Involved in cell cycle regulation, apoptosis, and splicing regulation^Citation35^–^Citation37
MKI67			X	X		Involved in cellular proliferation
MMP11			X	X		Involved in extracellular matrix breakdown
MYBL2a		X	X	X		Encodes a nuclear protein; involved in cell cycle progression
NDC80				X	X	Organization and stabilization of microtubule–kinetochore attachments
ORC6a		X		X	X	Involved in chromosome replication and segregation
PGR			X	X		Encodes a progesterone receptor; mediates effects of progesterone
RACGAP1	X	X				Involved in cytokinesis initiation and control of cellular growth
RFC4		X			X	Required for elongation of primed DNA templates
RRM2	X		X			Catalyzes the formation of deoxyribonucleotides from ribonucleotides
SCUBE2			X		X	Potential breast tumor suppressor gene^Citation38

Notes: Information on gene function was obtained from the NCBI’s Gene Database³⁹ unless noted otherwise.

a Indicates a gene used in three expression profiles.

Abbreviation: NCBI, National Center for Biotechnology Information.

ZhangYSchnabelCASchroederBEBreast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrenceClin Cancer Res201319154196420523757354

 PubMed Web of Science ®Google Scholar

SgroiDCSestakICuzickJPrediction of late distant recurrence in patients with oestrogen-receptor positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study populationLancet Oncol201314111067107624035531

 PubMed Web of Science ®Google Scholar

TuttAWangARowlandCRisk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signatureBMC Cancer2008833919025599

 PubMed Web of Science ®Google Scholar

Genomic Health®, IncOncotype DX^® Breast Cancer Assay Invasive Sales Aid Available from: http://breast-cancer.oncotypedx.com/en-US/Professional-Invasive/~/media/ODX-Breast/Images/Invasive/Invasive-SalesAid_11-2.pdfAccessed November 3, 2016

 Google Scholar

Genomic Health®, IncOncotype DX^® Breast Cancer Assay DCIS Sales Aid Available from: http://breast-cancer.oncotypedx.com/en-US/Professional-DCIS/~/media/ODX-Breast/Files/Downloads/DCIS_Sales_Aid.pdfAccessed November 13, 2015

 Google Scholar

NanoString Technologies®, IncPackage Insert Prosigna^® Breast Cancer Prognostic Gene Signature Assay Available from: http://prosigna.com/docs/Prosigna_Packet_Insert_US.pdfAccessed October 5, 2015

 Google Scholar

Agendia®Mammaprint^® 70-Gene Breast Cancer Recurrence Assay Available from: http://www.agendia.com/healthcare-professionals/breast-cancer/mammaprint/Accessed November 12, 2015

 Google Scholar

HornDZhouWTrevissonEThe conserved mitochondrial twin Cx9C protein Cmc2 Is a Cmc1 homologue essential for cytochrome coxidase biogenesisJ Biol Chem201028520150881509920220131

 PubMed Web of Science ®Google Scholar

VulstekeVBeullensMBoudrezAInhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1J Biol Chem2004279108642864714699119

 PubMed Web of Science ®Google Scholar

BeullensMVancauwenberghSMorriceNSubstrate specificity and activity regulation of protein kinase MELKJ Biol Chem200528048400034001116216881

 PubMed Web of Science ®Google Scholar

LinYCChenCCChengCJYangRBDomain and functional analysis of a novel breast tumor suppressor protein, SCUBE2J Biol Chem201128630270392704721652720

 PubMed Web of Science ®Google Scholar

NCBI Resource CoordinatorsDatabase resources of the National Center for Biotechnology InformationNucleic Acids Res201543Database issueD61725398906

 PubMed Web of Science ®Google Scholar