Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Jia-Min B. Pang, Peter Savas, Andrew P. Fellowes, Gisela Mir Arnau, Tanjina Kader, Ravikiran Vedururu, Chelsee Hewitt, Elena A. Takano, David J. Byrne, David Y. H. Choong, Ewan K. A. Millar, C. Soon Lee, Sandra A. O’Toole, Sunil R. Lakhani, Margaret C. Cummings, G. Bruce Mann, Ian G. Campbell, Alexander Dobrovic, Sherene Loi, Kylie L. GorringeStephen B. Fox

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)952-963
Number of pages12
JournalModern Pathology
Volume30
DOIs
Publication statusPublished - 2017

Open Access - Access Right Statement

©The Author(s) 2017. This work is licensed under a Creative Commons Attribution-NonCommercialNoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/ by-nc-nd/4.0/

Keywords

  • breast cancer
  • genetic sequencing
  • genomics
  • mutation
  • tumors

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