Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers.
| Title: | Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers. |
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| Authors: | Li X; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Yale Cancer Center, Breast Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, Rm133, New Haven, CT, 06511, USA.; Kumar S; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Harmanci A; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center Houston, Houston, TX, USA.; Li S; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Kitchen RR; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Zhang Y; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA.; The Ohio State University Comprehensive Cancer Center (OSUCCC - James), Columbus, OH, USA.; Wali VB; Yale Cancer Center, Breast Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, Rm133, New Haven, CT, 06511, USA.; Reddy SM; Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Woodward WA; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Reuben JM; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Rozowsky J; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA.; Hatzis C; Yale Cancer Center, Breast Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, Rm133, New Haven, CT, 06511, USA.; Ueno NT; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Krishnamurthy S; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. skrishna@mdanderson.org.; Pusztai L; Yale Cancer Center, Breast Medical Oncology, Yale School of Medicine, 300 George Street, Suite 120, Rm133, New Haven, CT, 06511, USA. lajos.pusztai@yale.edu.; Gerstein M; Program in Computational Biology and Bioinformatics, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA. mark@gersteinlab.org.; Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA. mark@gersteinlab.org.; Department of Computer Science, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA. mark@gersteinlab.org.; Department of Statistics and Data Science, Yale University, 266 Whitney Ave., Bass 432A, New Haven, CT, 06520, USA. mark@gersteinlab.org. |
| Source: | Genome medicine [Genome Med] 2021 Apr 26; Vol. 13 (1), pp. 70. Date of Electronic Publication: 2021 Apr 26. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : BioMed Central |
| MeSH Terms: | Genome, Human* ; Whole Genome Sequencing*; Inflammatory Breast Neoplasms/*genetics ; Mutation/*genetics; DNA Copy Number Variations/genetics ; Inflammatory Breast Neoplasms/microbiology ; Inflammatory Breast Neoplasms/pathology ; Signal Transduction/genetics ; Clone Cells ; Evolution, Molecular ; Humans ; Molecular Sequence Annotation ; Phenotype |
| 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. |
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| Grant Information: | R01 HG008126 United States HG NHGRI NIH HHS; T32 CA009666 United States CA NCI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS |
| Contributed Indexing: | Keywords: Copy number variant; Inflammatory breast cancer; Single nucleotide variant; Structural variant; Whole-genome sequencing |
| Entry Date(s): | Date Created: 20210427 Date Completed: 20220118 Latest Revision: 20240402 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8077918 |
| DOI: | 10.1186/s13073-021-00879-x |
| PMID: | 33902690 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't