Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer.
The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.
Jia-Min B
JB
Pang
Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Peter
P
Savas
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Andrew P
AP
Fellowes
Molecular Genomics Core, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Gisela
G
Mir Arnau
Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.|Cancer Genomics Program, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Tanjina
T
Kader
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Ravikiran
0000-0002-8816-1807
R
Vedururu
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Chelsee
C
Hewitt
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Elena A
EA
Takano
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
David J
DJ
Byrne
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
David Yh
DY
Choong
Translational Breast Cancer Research, The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.|Department of Anatomical Pathology, South Eastern Area Pathology Service, St George Hospital, Kogarah, NSW, Australia.|School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia.|Discipline of Pathology, School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia.
Ewan Ka
EK
Millar
Discipline of Pathology, School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.|Cancer Pathology, Bosch Institute, University of Sydney, Camperdown, NSW, Australia.
C Soon
CS
Lee
Translational Breast Cancer Research, The Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
Sandra A
SA
O'Toole
School of Medicine and UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia.|Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Australia.
Sunil R
0000-0003-1879-2555
SR
Lakhani
School of Medicine and UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia.|Pathology Queensland, The Royal Brisbane and Women's Hospital, Brisbane, Australia.
Margaret C
MC
Cummings
Breast Service, The Royal Melbourne and Royal Women's Hospitals, Parkville, VIC, Australia.|Department of Surgery, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.
G Bruce
GB
Mann
Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.|Cancer Genomics Program, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Ian G
IG
Campbell
Translational Genomics &Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
Alexander
A
Dobrovic
Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.
Sherene
S
Loi
Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.|Cancer Genomics Program, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.
Kylie L
0000-0001-5681-2022
KL
Gorringe
Department of Pathology, Peter MacCallum Cancer Centre, Grattan Street, Melbourne, VIC, Australia.|Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, Australia.
Stephen B
0000-0002-7648-8896
SB
Fox
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D058534:Class I Phosphatidylinositol 3-Kinases; D050990:GATA3 Transcription Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C494749:GATA3 protein, human; C495901:TP53 protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human