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Comprehensive molecular portraits of human breast tumours
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Journal Article
Comprehensive molecular portraits of human breast tumours
2012
Overview
We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (
TP53
,
PIK3CA
and
GATA3
) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in
GATA3
,
PIK3CA
and
MAP3K1
with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (
TP53
,
PIK3CA
and
GATA3
) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.
Gene variation in breast cancer
This Article from the Cancer Genome Atlas consortium describes a multifaceted analysis of primary breast cancers in 825 people. Exome sequencing, copy number variation, DNA methylation, messenger RNA arrays, microRNA sequencing and proteomic analyses were performed and integrated to shed light on breast-cancer heterogeneity. Just three genes —
TP53
,
PIK3CA
and
GATA3
— are mutated at greater than 10% frequency across all breast cancers. Many subtype-associated and novel mutations were identified, as well as two breast-cancer subgroups with specific signalling-pathway signatures. The analyses also suggest that much of the clinically observable plasticity and heterogeneity occurs within, and not across, the major subtypes of breast cancer.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 631/337
/ Biological and medical sciences
/ Breast Neoplasms - classification
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Class I Phosphatidylinositol 3-Kinases
/ DNA
/ DNA Copy Number Variations - genetics
/ Female
/ GATA3 Transcription Factor - genetics
/ Gene Expression Regulation, Neoplastic
/ Genetics
/ Genomics
/ Genòmica
/ Gynecology. Andrology. Obstetrics
/ Humanities and Social Sciences
/ Humans
/ Identification and classification
/ MAP Kinase Kinase Kinase 1 - genetics
/ Mutation
/ Oligonucleotide Array Sequence Analysis
/ Oncology
/ Ovarian Neoplasms - genetics
/ Ovarian Neoplasms - pathology
/ Phosphatidylinositol 3-Kinases - genetics
/ Proteins
/ Receptors, Estrogen - metabolism
/ Retinoblastoma Protein - genetics
/ Retinoblastoma Protein - metabolism
/ Science
/ Tumors
