논문요약

Main questions #

다양한 분석 플랫폼(CNV, Exome sequencing, mRNA expression, microRNA expression, protein expression)을 통합하여 유방암 서브타입별(ER+, HER2+, TNBC(Basal-like)) 분자적 메카니즘 규명

Materials and methods #

Tumor and germline DNA from 825 patients

• Agilent mRNA expresion microarrays (n=547)
  • SigClust analysis
  • Semi-supervised hierarchical clustering
  • 50 genes PAM50 model clissification
• Illumina Infinium DNA methylation chips (n=802, 1222 miRBase)
  • Unsupervised clustering analysis
• Affymetrix Genome-Wide Human SNP Array 6.0 (n=773)
  • GISTIC
• microRNA sequencing (n=697)
• Exome sequencing (n=507)
  • Condel, MuSiC 프로그램으로 유의한 변이 유전자 확인
• Reverse Phase Protein Array (n=403)
  • Unsupervised hierarchical clustering analysis

Integrated analysis

• PARADIGM analysis for patient-specific pathway activites
• MEMo analysis to identify multually exclusive alterations targetting frequently altered genes likely to belong to the same pathway

And 17 months Survival analysis

Refer TCGA Data summary

Main finding of the paper #

Significantly mutated genes in breast cancer #

507 환자 WES로 부터 30,626 somatic mutation 찾음. RNA 부분에 819개가 있으며 619개가 기존의 COSMIC, OMIM에 보고되어 있음. 35개의 SMG(Significantly mutated genes)를 찾음.

Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers

Association between mutations and mRNA-expression subtypes #

Luminal A subtype harbored the most SMGs, with the most frequent being PIK3CA (45%), followed by MAP3K1, GATA3, TP53, CDH1, and MAP2K4.

Luminal B cancers exhibited a diversity of SMGs with TP53 and PIK3CA (29% each) being the most frequent.

TP53 mutations in Basal-like tumors were mostly nonsense and frame-shift, while missense mutations predominated in Luminal A and B tumors

Germline BRCA1 mutation is associated with basal-like breast cancers.

Gene expression analyses (mRNA and microRNA) #

There was little correlation with mutation status and microRNA subtype.

DNA methylation #

5 distinct DNA methylation groups.

A DAVID functional annotation analysis identified ‘Extracellular region part’ and ‘Wnt signaling pathway’ to be associated with this 490 gene-set; the Group 3 hyper-methylated samples showed fewer PIK3CA and MAP3K1 mutations, and lower expression of Wnt-pathway genes.

DNA copy number #

NMF clustering of GISTIC segments identified five copy number clusters/groups that correlated with mRNA-subtypes, ER, PR and HER2 clinical status, and TP53 mutation status

Reverse Phase Protein Arrays (RPPA) #

It identifies 7 subtypes

Multi-platform subtype discovery #

Luminal/ER-positive summary analysis #

Across all breast cancers, MEMo identified a set of modules that highlight the differential activation events within the Receptor tyrosine kinase (RTK)/PI3K pathway; mutations of PIK3CA were very common in Luminal/ER-positive cancers while PTEN loss was more common in Basal-like tumors.

HER2-based classifications and summary analysis #

Many therapeutic advances have been made for clinically HER2-positive disease. This study has identified additional somatic mutations that represent potential therapeutic targets within this group, including

1. a high frequency of PIK3CA mutations (39%)
2. a lower frequency of PTEN and PIK3R1 mutations (Supplemental Table 6)
3. genomic losses of PTEN and INPP4B.

Other possible druggable mutations included variants within HER-family members including two somatic mutations in HER2, two within HER1/EGFR, and five within HER3.

Pertuzumab, in combination with Trastuzumab, targets the HER2-HER3 heterodimer48, however, these data suggest that targeting HER1 with HER2 could also be beneficial. Lastly, the HER2E-mRNA-subtype typically showed high aneuploidy, the highest somatic mutation rate (Table 1), and DNA amplification of other potential therapeutic targets including FGFRs, HER1/EGFR, CDK4 and Cyclin D1.

Basial-like summary analysis #

Basal-like tumors showed a high frequency of TP53 mutations (80%). In addition to loss of TP53, a MEMo analysis reconfirmed that loss of RB1 and BRCA1 are Basal-like features

Remaining questions to be addressed #

The biological insight that could be gained from this study #

관련자료 #

• 요약발표 by Hyungyong Kim 2015-01-22

Incoming Links #

Related Medical Conditions (MedicalCondition 0) #

• Breast cancer

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