Genomic landscape of ductal carcinoma in situ and association with progression

Chieh Yu Lin; Sujay Vennam; Natasha Purington; Eric Lin; Sushama Varma; Summer Han; Manisha Desa; Tina Seto; Nicholas J. Wang; Henning Stehr; Megan L. Troxell; Allison W. Kurian; Robert B. West

doi:10.1007/s10549-019-05401-x

Genomic landscape of ductal carcinoma in situ and association with progression

Chieh Yu Lin
, Sujay Vennam
, Natasha Purington
, Eric Lin
, Sushama Varma
, Summer Han
, Manisha Desa
, Tina Seto
, Nicholas J. Wang
, Henning Stehr
, Megan L. Troxell
, Allison W. Kurian
, Robert B. West

Pathology

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Purpose: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. Methods: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. Results: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). Conclusions: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

Original language	English (US)
Pages (from-to)	307-316
Number of pages	10
Journal	Breast Cancer Research and Treatment
Volume	178
Issue number	2
DOIs	https://doi.org/10.1007/s10549-019-05401-x
State	Published - Nov 1 2019

Funding

This work is supported by NIH R01CA193694, the Susan and Richard Levy Gift Fund; the Suzanne Pride Bryan Fund for Breast Cancer Research; the Breast Cancer Research Foundation; the Jan Weimer Junior Faculty Chair in Breast Oncology; the BRCA Foundation; and the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California. The project was supported by an NIH CTSA award number UL1 RR025744. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors, and endorsements by the University or State of California, the California Department of Health Services, the National Cancer Institute, or the Centers for Disease Control and Prevention or their contractors and subcontractors are neither intentional nor should be inferred. Short-read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. We thank Norman Cyr for his artistic contribution to Fig.?2.

Funders	Funder number
BRCA Foundation
California Department of Health Services
National Cancer Institute’s Surveillance, Epidemiology and End Results Program	UL1 RR025744
Susan and Richard Levy Gift Fund
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute of Health-National Cancer Institute	R01CA193694, 1U58 DP000807-01
National Center for Research Resources	UL1RR025744
Breast Cancer Research Foundation
Oregon State University/Oregon Health and Science University

Keywords

Breast cancer
Copy number variant
Ductal carcinoma in situ
PIK3CA

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1007/s10549-019-05401-x

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title = "Genomic landscape of ductal carcinoma in situ and association with progression",

abstract = "Purpose: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. Methods: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. Results: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4\%) and TP53 (18.4\%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). Conclusions: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.",

keywords = "Breast cancer, Copy number variant, Ductal carcinoma in situ, PIK3CA",

author = "Lin, \{Chieh Yu\} and Sujay Vennam and Natasha Purington and Eric Lin and Sushama Varma and Summer Han and Manisha Desa and Tina Seto and Wang, \{Nicholas J.\} and Henning Stehr and Troxell, \{Megan L.\} and Kurian, \{Allison W.\} and West, \{Robert B.\}",

note = "Publisher Copyright: {\textcopyright} 2019, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2019",

month = nov,

day = "1",

doi = "10.1007/s10549-019-05401-x",

language = "English (US)",

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T1 - Genomic landscape of ductal carcinoma in situ and association with progression

AU - Lin, Chieh Yu

AU - Vennam, Sujay

AU - Purington, Natasha

AU - Lin, Eric

AU - Varma, Sushama

AU - Han, Summer

AU - Desa, Manisha

AU - Seto, Tina

AU - Wang, Nicholas J.

AU - Stehr, Henning

AU - Troxell, Megan L.

AU - Kurian, Allison W.

AU - West, Robert B.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Purpose: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. Methods: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. Results: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). Conclusions: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

AB - Purpose: The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. Methods: Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. Results: We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). Conclusions: PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

KW - Breast cancer

KW - Copy number variant

KW - Ductal carcinoma in situ

KW - PIK3CA

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DO - 10.1007/s10549-019-05401-x

M3 - Article

AN - SCOPUS:85071030760

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VL - 178

SP - 307

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JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 2

ER -

Genomic landscape of ductal carcinoma in situ and association with progression

Abstract

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Keywords

ASJC Scopus subject areas

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