Dataset Information

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

ABSTRACT: Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR?+?/HER2?- tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.

SUBMITTER: Pitt JJ

PROVIDER: S-EPMC6191428 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Pitt Jason J JJ Riester Markus M Zheng Yonglan Y Yoshimatsu Toshio F TF Sanni Ayodele A Oluwasola Olayiwola O Veloso Artur A Labrot Emma E Wang Shengfeng S Odetunde Abayomi A Ademola Adeyinka A Okedere Babajide B Mahan Scott S Leary Rebecca R Macomber Maura M Ajani Mustapha M Johnson Ryan S RS Fitzgerald Dominic D Grundstad A Jason AJ Tuteja Jigyasa H JH Khramtsova Galina G Zhang Jing J Sveen Elisabeth E Hwang Bryce B Clayton Wendy W Nkwodimmah Chibuzor C Famooto Bisola B Obasi Esther E Aderoju Victor V Oludara Mobolaji M Omodele Folusho F Akinyele Odunayo O Adeoye Adewunmi A Ogundiran Temidayo T Babalola Chinedum C MacIsaac Kenzie K Popoola Abiodun A Morrissey Michael P MP Chen Lin S LS Wang Jiebiao J Olopade Christopher O CO Falusi Adeyinka G AG Winckler Wendy W Haase Kerstin K Van Loo Peter P Obafunwa John J Papoutsakis Dimitris D Ojengbede Oladosu O Weber Barbara B Ibrahim Nasiru N White Kevin P KP Huo Dezheng D Olopade Olufunmilayo I OI Barretina Jordi J

Nature communications 20181016 1

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mu ...[more]

PMID: 30327465

Similar Datasets

Project description:BackgroundUterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.MethodsA cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting.ResultsAll 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.ConclusionsOur work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

Dataset Information

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Publications

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets