MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Histone Proteomic Networks

Sean Hacking; Charissa Chou; Yigit Baykara; Yihong Wang; Alper Uzun; Ece D Gamsiz Uzun

doi:10.3390/ijms24065327

MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Histone Proteomic Networks

Int J Mol Sci. 2023 Mar 10;24(6):5327. doi: 10.3390/ijms24065327.

Authors

Sean Hacking^{1

2}, Charissa Chou^{1

3}, Yigit Baykara^{1

2}, Yihong Wang^{1

2}, Alper Uzun^{4

5

6}, Ece D Gamsiz Uzun^{1

2

6}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Providence, RI 02903, USA.
² Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
³ Department of Biology, Brown University, Providence, RI 02912, USA.
⁴ Legorreta Cancer Center, Brown University, Providence, RI 02912, USA.
⁵ Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
⁶ Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA.

Abstract

Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes, including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR are largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare and only seen to occur in around 3% of BCs. In the present study, we analyzed TCGA data using a multi-sample protein-protein interaction (PPI) analysis tool, Proteinarium, and showed a distinct separation between specific MMR-deficient and -intact networks in a cohort of 994 BC patients. In the PPI networks specific to MMR deficiency, highly connected clusters of histone genes were identified. We also found the distribution of MMR-deficient BC to be more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. We recommend defining MMR-deficient BC by next-generation sequencing (NGS) when any somatic mutation is detected in one of the seven MMR genes.

Keywords: MMR; Proteinarium; breast cancer; comprehensive genomic profiling; histone proteins.

MeSH terms

Brain Neoplasms
Colorectal Neoplasms*
DNA Mismatch Repair / genetics
Histones / genetics
Humans
Neoplastic Syndromes, Hereditary
Proteomics
Triple Negative Breast Neoplasms* / genetics

Substances

Histones

Supplementary concepts

Turcot syndrome

Grants and funding

C.C. was supported by a Brown University SPRINT award for research. E.D.G.U. and A.U. were supported by the Brown University Legorreta Cancer Center and Rhode Island Foundation (#11915_20221326).