Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations

Elena Guerini Rocco, Salvatore Piscuoglio, Charlotte K Y Ng, Felipe C. Geyer, Maria R. De Filippo, Carey A. Eberle, Muzaffar Akram, Nicola Fusco, Shu Ichihara, Rita Sakr, Yasushi Yatabe, Anne Vincent-Salomon, Emad A. Rakha, Ian O. Ellis, Y. Hannah Wen, Britta Weigelt, Stuart J. Schnitt, Jorge S. Reis-Filho

Research output: Contribution to journalArticle

Abstract

Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.

Original languageEnglish
Pages (from-to)677-688
Number of pages12
JournalJournal of Pathology
Volume238
Issue number5
DOIs
Publication statusPublished - Apr 1 2016

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Fibrocystic Breast Disease
Triple Negative Breast Neoplasms
Phenotype
Mutation
Genes
High-Throughput Nucleotide Sequencing
Gene Dosage
Neoplasm Genes
Receptor Protein-Tyrosine Kinases
Progesterone Receptors
Phosphatidylinositol 3-Kinases
DNA Repair
Estrogen Receptors
Breast
Epithelial Cells

Keywords

  • breast cancer precursor
  • mutations
  • targeted capture massively parallel sequencing
  • TP53
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations. / Guerini Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Geyer, Felipe C.; De Filippo, Maria R.; Eberle, Carey A.; Akram, Muzaffar; Fusco, Nicola; Ichihara, Shu; Sakr, Rita; Yatabe, Yasushi; Vincent-Salomon, Anne; Rakha, Emad A.; Ellis, Ian O.; Wen, Y. Hannah; Weigelt, Britta; Schnitt, Stuart J.; Reis-Filho, Jorge S.

In: Journal of Pathology, Vol. 238, No. 5, 01.04.2016, p. 677-688.

Research output: Contribution to journalArticle

Guerini Rocco, E, Piscuoglio, S, Ng, CKY, Geyer, FC, De Filippo, MR, Eberle, CA, Akram, M, Fusco, N, Ichihara, S, Sakr, R, Yatabe, Y, Vincent-Salomon, A, Rakha, EA, Ellis, IO, Wen, YH, Weigelt, B, Schnitt, SJ & Reis-Filho, JS 2016, 'Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations', Journal of Pathology, vol. 238, no. 5, pp. 677-688. https://doi.org/10.1002/path.4691
Guerini Rocco, Elena ; Piscuoglio, Salvatore ; Ng, Charlotte K Y ; Geyer, Felipe C. ; De Filippo, Maria R. ; Eberle, Carey A. ; Akram, Muzaffar ; Fusco, Nicola ; Ichihara, Shu ; Sakr, Rita ; Yatabe, Yasushi ; Vincent-Salomon, Anne ; Rakha, Emad A. ; Ellis, Ian O. ; Wen, Y. Hannah ; Weigelt, Britta ; Schnitt, Stuart J. ; Reis-Filho, Jorge S. / Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations. In: Journal of Pathology. 2016 ; Vol. 238, No. 5. pp. 677-688.
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T1 - Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations

AU - Guerini Rocco, Elena

AU - Piscuoglio, Salvatore

AU - Ng, Charlotte K Y

AU - Geyer, Felipe C.

AU - De Filippo, Maria R.

AU - Eberle, Carey A.

AU - Akram, Muzaffar

AU - Fusco, Nicola

AU - Ichihara, Shu

AU - Sakr, Rita

AU - Yatabe, Yasushi

AU - Vincent-Salomon, Anne

AU - Rakha, Emad A.

AU - Ellis, Ian O.

AU - Wen, Y. Hannah

AU - Weigelt, Britta

AU - Schnitt, Stuart J.

AU - Reis-Filho, Jorge S.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.

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KW - breast cancer precursor

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KW - targeted capture massively parallel sequencing

KW - TP53

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