Whole-exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component

Bracha Erlanger Avigdor, Katie Beierl, Christopher Gocke, Daniel J. Zabransky, Karen Cravero, Kelly Kyker-Snowman, Berry Button, David Chu, Sarah Croessmann, Rory L. Cochran, Roisin Connolly, Ben H. Park, Sarah Wheelan, Ashley M Cimino-Mathews

Research output: Contribution to journalArticle

Abstract

Purpose: Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor, and HER-2 amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. Experimental Design: We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in 8 patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments. Results: In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence. Conclusions: A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers.

Original languageEnglish (US)
Pages (from-to)4875-4884
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

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Exome
Ductal Carcinoma
Breast Neoplasms
Histology
Neoplasms
Epigenomics
Progesterone Receptors
Estrogen Receptors
Research Design
Carcinoma
Phenotype
Mutation
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Whole-exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component. / Avigdor, Bracha Erlanger; Beierl, Katie; Gocke, Christopher; Zabransky, Daniel J.; Cravero, Karen; Kyker-Snowman, Kelly; Button, Berry; Chu, David; Croessmann, Sarah; Cochran, Rory L.; Connolly, Roisin; Park, Ben H.; Wheelan, Sarah; Cimino-Mathews, Ashley M.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4875-4884.

Research output: Contribution to journalArticle

Avigdor, BE, Beierl, K, Gocke, C, Zabransky, DJ, Cravero, K, Kyker-Snowman, K, Button, B, Chu, D, Croessmann, S, Cochran, RL, Connolly, R, Park, BH, Wheelan, S & Cimino-Mathews, AM 2017, 'Whole-exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component', Clinical Cancer Research, vol. 23, no. 16, pp. 4875-4884. https://doi.org/10.1158/1078-0432.CCR-17-0108
Avigdor, Bracha Erlanger ; Beierl, Katie ; Gocke, Christopher ; Zabransky, Daniel J. ; Cravero, Karen ; Kyker-Snowman, Kelly ; Button, Berry ; Chu, David ; Croessmann, Sarah ; Cochran, Rory L. ; Connolly, Roisin ; Park, Ben H. ; Wheelan, Sarah ; Cimino-Mathews, Ashley M. / Whole-exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4875-4884.
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T1 - Whole-exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component

AU - Avigdor, Bracha Erlanger

AU - Beierl, Katie

AU - Gocke, Christopher

AU - Zabransky, Daniel J.

AU - Cravero, Karen

AU - Kyker-Snowman, Kelly

AU - Button, Berry

AU - Chu, David

AU - Croessmann, Sarah

AU - Cochran, Rory L.

AU - Connolly, Roisin

AU - Park, Ben H.

AU - Wheelan, Sarah

AU - Cimino-Mathews, Ashley M

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N2 - Purpose: Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor, and HER-2 amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. Experimental Design: We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in 8 patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments. Results: In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence. Conclusions: A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers.

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