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Integrative genomic and transcriptomic characterization of papillary carcinomas of the breast

View Article: PubMed Central - PubMed

ABSTRACT

Papillary carcinoma (PC) is a rare type of breast cancer, which comprises three histologic subtypes: encapsulated PC (EPC), solid PC (SPC) and invasive PC (IPC). Microarray-based gene expression and Affymetrix SNP 6.0 gene copy number profiling, and RNA-sequencing revealed that PCs are luminal breast cancers that display transcriptomic profiles distinct from those of grade- and estrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs), and that the papillary histologic pattern is unlikely to be underpinned by a highly recurrent expressed fusion gene or a highly recurrent expressed mutation. Despite displaying similar patterns of gene copy number alterations, significant differences in the transcriptomic profiles of EPCs, SPCs and IPCs were found, and may account for their different histologic features.

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Schematic representation of 4 validated fusion genes in papillary carcinomas of the breast. (A) USF1-CCDC38. (B) VLC-ADK. (C) SARNP-PAN2. (D) MAPKAPK3-HEMK1.
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fig4: Schematic representation of 4 validated fusion genes in papillary carcinomas of the breast. (A) USF1-CCDC38. (B) VLC-ADK. (C) SARNP-PAN2. (D) MAPKAPK3-HEMK1.

Mentions: We next sought to identify potential gain-of-function fusion genes that may underpin PCs. In a way akin to the oncogenic fusion genes identified in special histologic types of breast cancer, leukemias, lymphomas and sarcomas, we prioritized fusion transcripts that were identified by both algorithms, involved open reading frames with known associated functions, and that harbored intact functional domains. Using the above criteria, we identified 14 in-frame fusion transcripts, 12 of which were successfully validated by RT-PCR (Figure 4, Supplementary Figure S4; Supplementary Table S10). These validated fusion transcripts did not map to regions harboring amplifications and were only detected and validated in the index cases. Only one of these confirmed fusion transcripts, MAPKAPK3-HEMK1, harbored intact functional domains encoded by the first 4 exons of the protein kinase MAPKAPK3 and the last 7 exons of the methyltransferase HEMK1 (Figure 4D). In addition to the kinase domain, this chimeric transcript has a conserved DNA methylase domain, which has been reported to methylate the mitochondrial translation release factor MTRF1L (Ishizawa et al., 2008). Taken together, our results demonstrate that PCs are not underpinned by a highly recurrent fusion gene, at variance with some other special histological types of breast cancer.


Integrative genomic and transcriptomic characterization of papillary carcinomas of the breast
Schematic representation of 4 validated fusion genes in papillary carcinomas of the breast. (A) USF1-CCDC38. (B) VLC-ADK. (C) SARNP-PAN2. (D) MAPKAPK3-HEMK1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037246&req=5

fig4: Schematic representation of 4 validated fusion genes in papillary carcinomas of the breast. (A) USF1-CCDC38. (B) VLC-ADK. (C) SARNP-PAN2. (D) MAPKAPK3-HEMK1.
Mentions: We next sought to identify potential gain-of-function fusion genes that may underpin PCs. In a way akin to the oncogenic fusion genes identified in special histologic types of breast cancer, leukemias, lymphomas and sarcomas, we prioritized fusion transcripts that were identified by both algorithms, involved open reading frames with known associated functions, and that harbored intact functional domains. Using the above criteria, we identified 14 in-frame fusion transcripts, 12 of which were successfully validated by RT-PCR (Figure 4, Supplementary Figure S4; Supplementary Table S10). These validated fusion transcripts did not map to regions harboring amplifications and were only detected and validated in the index cases. Only one of these confirmed fusion transcripts, MAPKAPK3-HEMK1, harbored intact functional domains encoded by the first 4 exons of the protein kinase MAPKAPK3 and the last 7 exons of the methyltransferase HEMK1 (Figure 4D). In addition to the kinase domain, this chimeric transcript has a conserved DNA methylase domain, which has been reported to methylate the mitochondrial translation release factor MTRF1L (Ishizawa et al., 2008). Taken together, our results demonstrate that PCs are not underpinned by a highly recurrent fusion gene, at variance with some other special histological types of breast cancer.

View Article: PubMed Central - PubMed

ABSTRACT

Papillary carcinoma (PC) is a rare type of breast cancer, which comprises three histologic subtypes: encapsulated PC (EPC), solid PC (SPC) and invasive PC (IPC). Microarray-based gene expression and Affymetrix SNP 6.0 gene copy number profiling, and RNA-sequencing revealed that PCs are luminal breast cancers that display transcriptomic profiles distinct from those of grade- and estrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs), and that the papillary histologic pattern is unlikely to be underpinned by a highly recurrent expressed fusion gene or a highly recurrent expressed mutation. Despite displaying similar patterns of gene copy number alterations, significant differences in the transcriptomic profiles of EPCs, SPCs and IPCs were found, and may account for their different histologic features.

No MeSH data available.


Related in: MedlinePlus