Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

Mari K Halle; Aishwarya Sundaresan; Jianqing Zhang; Chandra Sekhar Pedamallu; Vinodh Srinivasasainagendra; Jessica Blair; Dewey Brooke; Bjørn I Bertelsen; Kathrine Woie; Sadeep Shrestha; Hemant Tiwari; Yick Fu Wong; Camilla Krakstad; Akinyemi I Ojesina

doi:10.1038/s41525-021-00244-2

Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

NPJ Genom Med. 2021 Oct 7;6(1):82. doi: 10.1038/s41525-021-00244-2.

Authors

Mari K Halle^{1

2

3}, Aishwarya Sundaresan⁴, Jianqing Zhang³, Chandra Sekhar Pedamallu³, Vinodh Srinivasasainagendra⁴, Jessica Blair³, Dewey Brooke³, Bjørn I Bertelsen⁵, Kathrine Woie¹, Sadeep Shrestha³, Hemant Tiwari⁴, Yick Fu Wong⁶, Camilla Krakstad^#^{7

8}, Akinyemi I Ojesina^#^{9

10

11}

Affiliations

¹ Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway.
² Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
³ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
⁶ Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
⁷ Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway. [email protected].
⁸ Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway. [email protected].
⁹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA. [email protected].
¹⁰ O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. [email protected].
¹¹ HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA. [email protected].

^# Contributed equally.

Abstract

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.

Abstract

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