Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers
Abstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired...
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2021-04-01
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Online Access: | https://doi.org/10.1186/s13073-021-00879-x |
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doaj-1add699a6a154a93abe43aacbd318851 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaotong Li Sushant Kumar Arif Harmanci Shantao Li Robert R. Kitchen Yan Zhang Vikram B. Wali Sangeetha M. Reddy Wendy A. Woodward James M. Reuben Joel Rozowsky Christos Hatzis Naoto T. Ueno Savitri Krishnamurthy Lajos Pusztai Mark Gerstein |
spellingShingle |
Xiaotong Li Sushant Kumar Arif Harmanci Shantao Li Robert R. Kitchen Yan Zhang Vikram B. Wali Sangeetha M. Reddy Wendy A. Woodward James M. Reuben Joel Rozowsky Christos Hatzis Naoto T. Ueno Savitri Krishnamurthy Lajos Pusztai Mark Gerstein Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers Genome Medicine Inflammatory breast cancer Whole-genome sequencing Single nucleotide variant Copy number variant Structural variant |
author_facet |
Xiaotong Li Sushant Kumar Arif Harmanci Shantao Li Robert R. Kitchen Yan Zhang Vikram B. Wali Sangeetha M. Reddy Wendy A. Woodward James M. Reuben Joel Rozowsky Christos Hatzis Naoto T. Ueno Savitri Krishnamurthy Lajos Pusztai Mark Gerstein |
author_sort |
Xiaotong Li |
title |
Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
title_short |
Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
title_full |
Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
title_fullStr |
Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
title_full_unstemmed |
Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
title_sort |
whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2021-04-01 |
description |
Abstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Results Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Conclusions Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets. |
topic |
Inflammatory breast cancer Whole-genome sequencing Single nucleotide variant Copy number variant Structural variant |
url |
https://doi.org/10.1186/s13073-021-00879-x |
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doaj-1add699a6a154a93abe43aacbd3188512021-05-02T11:10:59ZengBMCGenome Medicine1756-994X2021-04-0113111410.1186/s13073-021-00879-xWhole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancersXiaotong Li0Sushant Kumar1Arif Harmanci2Shantao Li3Robert R. Kitchen4Yan Zhang5Vikram B. Wali6Sangeetha M. Reddy7Wendy A. Woodward8James M. Reuben9Joel Rozowsky10Christos Hatzis11Naoto T. Ueno12Savitri Krishnamurthy13Lajos Pusztai14Mark Gerstein15Program in Computational Biology and Bioinformatics, Yale UniversityProgram in Computational Biology and Bioinformatics, Yale UniversityCenter for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center HoustonProgram in Computational Biology and Bioinformatics, Yale UniversityProgram in Computational Biology and Bioinformatics, Yale UniversityProgram in Computational Biology and Bioinformatics, Yale UniversityYale Cancer Center, Breast Medical Oncology, Yale School of MedicineDivision of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical CenterMorgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer CenterMorgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer CenterProgram in Computational Biology and Bioinformatics, Yale UniversityYale Cancer Center, Breast Medical Oncology, Yale School of MedicineDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterMorgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer CenterYale Cancer Center, Breast Medical Oncology, Yale School of MedicineProgram in Computational Biology and Bioinformatics, Yale UniversityAbstract Background Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases. Methods We performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin). Results Overall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages. Conclusions Whole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.https://doi.org/10.1186/s13073-021-00879-xInflammatory breast cancerWhole-genome sequencingSingle nucleotide variantCopy number variantStructural variant |