Immune infiltration, aggressive pathology, and poor survival outcomes in RECQL helicase deficient breast cancers

Ayat Lashen; Abdulbaqi Al-Kawaz; Jennie N Jeyapalan; Shatha Alqahtani; Ahmed Shoqafi; Mashael Algethami; Michael Toss; Andrew R Green; Nigel P Mongan; Sudha Sharma; Mohammad R Akbari; Emad A Rakha; Srinivasan Madhusudan

doi:10.1016/j.neo.2023.100957

Immune infiltration, aggressive pathology, and poor survival outcomes in RECQL helicase deficient breast cancers

Neoplasia. 2024 Jan:47:100957. doi: 10.1016/j.neo.2023.100957. Epub 2023 Dec 21.

Affiliations

¹ Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK.
² Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK; Department of Pathology, Nottingham University Hospital, City Campus, Hucknall Road, Nottingham NG51PB, UK.
³ Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
⁴ Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, 520 W Street, NW, Washington, DC 20059, USA.
⁵ Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto. Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁶ Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, University Park, Nottingham NG7 3RD, UK; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.

Abstract

RECQL is essential for genomic stability. Here, we evaluated RECQL in 449 pure ductal carcinomas in situ (DCIS), 152 DCIS components of mixed DCIS/invasive breast cancer (IBC) tumors, 157 IBC components of mixed DCIS/IBC and 50 normal epithelial terminal ductal lobular units (TDLUs). In 726 IBCs, CD8+, FOXP3+, IL17+, PDL1+, PD1+ T-cell infiltration (TILs) were investigated in RECQL deficient and proficient cancers. Tumor mutation burden (TMB) was evaluated in five RECQL germ-line mutation carriers with IBC by genome sequencing. Compared with normal epithelial cells, a striking reduction in nuclear RECQL in DCIS was evident with aggressive pathology and poor survival. In RECQL deficient IBCs, CD8+, FOXP3+, IL17+ or PDL1+ TILs were linked with aggressive pathology and shorter survival. In germline RECQL mutation carriers, increased TMB was observed in 4/5 tumors. We conclude that RECQL loss is an early event in breast cancer and promote immune cell infiltration.

Keywords: Breast cancer; CD8; DCIS; FOXP3; IL17; Immune cell infiltration; Local recurrence; PD1; PDL1; RECQL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Breast Neoplasms* / pathology
Carcinoma, Intraductal, Noninfiltrating* / pathology
Female
Forkhead Transcription Factors / genetics
Genetic Predisposition to Disease
Humans
RecQ Helicases / genetics

Substances

RecQ Helicases
Biomarkers, Tumor
Forkhead Transcription Factors
RECQL protein, human