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 Troxell, Allison W. Kurian, Robert B. West

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jan 1 2019

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Carcinoma, Intraductal, Noninfiltrating
Breast Neoplasms
Mutation
Phosphotransferases
Logistic Models
Odds Ratio
Fluorescence In Situ Hybridization
Genes
Exons
Chromosomes
Demography

Keywords

  • Breast cancer
  • Copy number variant
  • Ductal carcinoma in situ
  • PIK3CA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lin, C. Y., Vennam, S., Purington, N., Lin, E., Varma, S., Han, S., ... West, R. B. (Accepted/In press). Genomic landscape of ductal carcinoma in situ and association with progression. Breast Cancer Research and Treatment. https://doi.org/10.1007/s10549-019-05401-x

Genomic landscape of ductal carcinoma in situ and association with progression. / Lin, Chieh Yu; Vennam, Sujay; Purington, Natasha; Lin, Eric; Varma, Sushama; Han, Summer; Desa, Manisha; Seto, Tina; Wang, Nicholas J.; Stehr, Henning; Troxell, Megan; Kurian, Allison W.; West, Robert B.

In: Breast Cancer Research and Treatment, 01.01.2019.

Research output: Contribution to journalArticle

Lin, CY, Vennam, S, Purington, N, Lin, E, Varma, S, Han, S, Desa, M, Seto, T, Wang, NJ, Stehr, H, Troxell, M, Kurian, AW & West, RB 2019, 'Genomic landscape of ductal carcinoma in situ and association with progression', Breast Cancer Research and Treatment. https://doi.org/10.1007/s10549-019-05401-x
Lin, Chieh Yu ; Vennam, Sujay ; Purington, Natasha ; Lin, Eric ; Varma, Sushama ; Han, Summer ; Desa, Manisha ; Seto, Tina ; Wang, Nicholas J. ; Stehr, Henning ; Troxell, Megan ; Kurian, Allison W. ; West, Robert B. / Genomic landscape of ductal carcinoma in situ and association with progression. In: Breast Cancer Research and Treatment. 2019.
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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

AU - Kurian, Allison W.

AU - West, Robert B.

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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.

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