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The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

ABSTRACT: Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

SUBMITTER: Pan JW

PROVIDER: S-EPMC7755902 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

Pan Jia-Wern JW Zabidi Muhammad Mamduh Ahmad MMA Ng Pei-Sze PS Meng Mei-Yee MY Hasan Siti Norhidayu SN Sandey Bethan B Sammut Stephen-John SJ Yip Cheng-Har CH Rajadurai Pathmanathan P Rueda Oscar M OM Caldas Carlos C Chin Suet-Feung SF Teo Soo-Hwang SH

Nature communications 20201222 1

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enr ...[more]

PMID: 33353943

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Project description:BackgroundWhole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer.Patients and methodsWe carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30).ResultsMatched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2.ConclusionsOur study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Project description:Purpose: Psychotic experiences in childhood (such as hearing voices or being suspicious) represent an important phenotype for early intervention. However, these experiences can be defined in several ways: self-reported psychotic experiences (SRPE) rely exclusively on the child's report, clinically validated psychotic experiences (CRPE) are based on clinical assessment, and attenuated psychotic symptoms (APS) represents a categorization to do with clinical relevance in relation to severity. Very few studies have investigated how these distinctions impact clinical and other domains. The present study aims to compare SRPE, CRPE, and APS among children and adolescents. Methods: This study is part of the Brazilian High-Risk Cohort Study for Psychiatric Disorders, in which 2,241 individuals aged 6-14 years provided self-ratings of 20 psychotic experiences using the Community Assessment of Psychic Experiences (CAPE). A trained psychologist conducted an interview to validate or reject reported experiences and to rate the presence of APS and affective flattening. In parallel, parents provided information about child mental health to an independent interviewer. We tested the association of mutually exclusive categories of non-validated SRPE (nSRPE), clinically validated PE below the threshold for APS (nCRPE), and APS (nSRPE = 33%, nCRPE = 11%, APS = 6%), with parents' information about the child's positive attributes and levels of psychopathology and psychologist assessment of blunted affect. Results: Most associations were qualitatively similar, and there was a dose-response in the strength of associations across categories, such that APS > nCRPE > nSRPE. Experiences in all three categories were associated with female sex. nSRPE were associated with overall levels of psychopathology, but to a lesser degree than nCRPE and APS. APS and nCRPE were associated with less positive attributes, with APS more so than nCRPE. Only APS was associated with affective flattening. Conclusions: In children and adolescents, SRPE, CRPE, and APS all index liability for psychopathology, but as clinician rated relevance increases, associations get stronger and become evident across more domains.

Project description:PurposeMale breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers.Experimental designAll male breast cancers were estrogen receptor-positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers.ResultsTwenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A-like or luminal B-like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair-related genes.ConclusionsMale breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045-56. ©2016 AACR.

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The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

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The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

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