Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13058-016-0758-5
Title: Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium
Authors: Muranen, T.A
Blomqvist, C
Dörk, T
Keywords: cadherin
cadherin 1
checkpoint kinase 2
estrogen receptor
progesterone receptor
protein p53
unclassified drug
checkpoint kinase 2
codon
transcriptome
tumor marker
adult
aged
Article
breast cancer
cancer grading
cancer mortality
cancer prognosis
cancer recurrence
cancer survival
CHEK2 gene
clinical feature
controlled study
distant metastasis
female
Finn (citizen)
gene expression profiling
gene mutation
heterozygote
histology
human
human tissue
major clinical study
protein expression
amino acid substitution
breast tumor
cancer staging
cluster analysis
codon
epidemiology
Europe
genetic association study
genetics
metastasis
missense mutation
mortality
pathology
prognosis
Amino Acid Substitution
Biomarkers, Tumor
Breast Neoplasms
Checkpoint Kinase 2
Cluster Analysis
Codon
Europe
Female
Gene Expression Profiling
Genetic Association Studies
Heterozygote
Humans
Mutation, Missense
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Prognosis
Transcriptome
Issue Date: 2016
Citation: Muranen, T.A, Blomqvist, C, Dörk, T (2016). Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium. Breast Cancer Research 18 (1) : 98. ScholarBank@NUS Repository. https://doi.org/10.1186/s13058-016-0758-5
Rights: Attribution 4.0 International
Abstract: Background: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. Methods: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. Results: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Conclusions: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations. @ 2016 The Author(s).
Source Title: Breast Cancer Research
URI: https://scholarbank.nus.edu.sg/handle/10635/183312
ISSN: 14655411
DOI: 10.1186/s13058-016-0758-5
Rights: Attribution 4.0 International
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