Biology subjects

Hasan, S. N.

Publications and source records attributed to Hasan, S. N..

5 recordsLinked to original sources

bioRxiv2024

CD3, CD4, and CD8 staining, but not PD-L1, are positively correlated with overall survival in Asian breast cancer

Given the fundamental importance of T lymphocytes in the effectiveness of cancer immunotherapy, and potentially in the response to chemotherapy and radiotherapy, immune cell markers have been evaluated as predictive and prognostic biomarkers, with conflicting results in the different subtypes of breast cancer and in different studies. In this study, we report the association of T lymphocyte markers with overall survival in a cross-sectional cohort of Asian breast cancer patients. Formalin-fixed, paraffin-embedded tumour samples from 576 breast cancer patients from a Malaysian hospital were stained with CD3, CD4, CD8 and PD-L1 antibodies, and area-based positive staining was quantified from digitized whole slide images. At a median follow up of 68 months, we report that CD3, CD4 and CD8 scores, but not PDL1 scores, were associated with overall survival, with the strongest associations seen in triple-negative breast cancer (TNBC). CD3, CD4, and CD8 scores were also compared to genomic and transcriptomic data from previous studies, and found to have a negative association with copy number aberrations, but no association with tumour mutational burden or neoantigen load. Taken together, T lymphocyte markers may be associated with good prognosis in Asian breast cancer patients.

cancer biology↗

bioRxiv2023

Clustering of HR+/HER2- breast cancer in an Asian cohort is driven by immune phenotypes

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR+/HER2-breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR+/HER2-breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR+/HER2-samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

cancer biology↗

bioRxiv2022

Gene signature for predicting homologous recombination deficiency in triple-negative breast cancer

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. Roughly 1 in 10 of TNBCs arise in individuals with pathogenic variants in BRCA1 or BRCA2, and treating BRCA-associated TNBCs with PARP inhibitors results in improved survival. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers, and we postulated that gene expression may identify individuals with such features who might also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we classified tumours as having high or low homologous recombination deficiency (HRD) and developed a gene expression-based machine learning classifier for HRD in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.94 in the MyBrCa validation dataset, and strongly segregated HRD-associated genomic features in TNBCs from TCGA and METABRIC. Further validation of the classifier using the NanoString nCounter platform showed that the RNA-seq results correlated strongly with NanoString results (r = 0.90) from fresh frozen tissue as well as NanoString results from FFPE tissue (r = 0.84). Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy. Novelty/Impact statementWe developed a gene expression-based classifier for homologous recombination deficiency (HRD) in breast cancer patients using WES and RNA-seq data obtained from 129 TNBC samples from a Malaysian hospital-based cohort (MyBrCa). This classifier was able to predict for HRD status at an AUC of 0.94 in the MyBrCa cohort, and was also able to segregate HRD-associated features in TNBCs from TCGA. We also validated the classifier on a NanoString platform with both fresh frozen and FFPE tissue.

cancer biology↗

bioRxiv2020

Germline APOBEC3B deletion in Asian women increases somatic hypermutation in breast cancer that is associated with Her2 subtype, PIK3CA mutations, immune activation, and increased survival

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/135251v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@45b329org.highwire.dtl.DTLVardef@1f5770corg.highwire.dtl.DTLVardef@5ac017org.highwire.dtl.DTLVardef@1f939ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

Molecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed 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 new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

cancer biology↗