Biomedical subjects

Ammal Abbasi

Publications and source records attributed to Ammal Abbasi.

3 recordsLinked to original sources

PubMed2026

Whole-Exome Sequencing Identifies Candidate Genomic Features Associated with Response to Platinum-Based Chemotherapy and Ixabepilone-Based Treatment in Ovarian Cancer.

Carboplatin/paclitaxel (CP) chemotherapy is the cornerstone of therapy for advanced stage ovarian cancer (OC). However, despite initial sensitivity, this regimen cannot avoid the emergence of resistance. Ixabepilone ± bevacizumab (IB) is a combination recently added to NCCN guidelines for the treatment of platinum-resistant OC. It would be desirable to identify biomarkers able to differentiate patients who are resistant to CP and IB, and biomarkers that identify which patients may benefit from IB treatment. We analyzed whole-exome-sequencing (WES) data from 49 OC patients exposed to CP, including 28 platinum-sensitive vs. 21 platinum-resistant, and 31 additional platinum-resistant patients, including 16 responders (i.e., CR/PR) vs. 15 non-responders (SD/PD) to ixabepilone ± bevacizumab. Comprehensive genetic analyses were performed to identify alterations correlated with resistance to CP and IB. WES analysis of CP responders vs. non-responders revealed differences in HRD-signatures (p < 0.05), OS (p < 0.005) and gain/loss-of-function in multiple genes associated with tumor growth/progression including but not limited to ACVR2A, INHBA, MAP3K7, ATG5, SGK1, FYN, RSPO3, NOD1 and LRRK2. WES analysis of platinum-resistant IB-treated patients revealed additional nominally significant genes and deranged pathways including gains in the DROSHA and SDHA genes in responders vs. non-responders (p < 0.05). Patients harboring HRD-signatures showed significantly higher sensitivity to CP and prolonged survival compared to HRD-negative patients. Alterations in genes associated with tumor growth/progression correlated with resistance to CP regimen and may represent novel "druggable" candidate biomarkers for the targeted treatment of CP/IB-resistant patients. Further validation in independent cohorts and preclinical experiments in CP/IB-resistant models are warranted to establish the clinical utility of these findings.

Humans↗

PubMed2026

Identification and validation of a previously missed mutational signature in colorectal cancer.

Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.

Colorectal Neoplasms↗

PubMed2025

Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer.

Mutational signature analysis has greatly enhanced our understanding of the mutagenic processes found in cancer and normal tissues. As part of a recent study, we analyzed 802 treatment-naïve, microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was conservatively decomposed into SBS18, a signature associated with reactive oxygen species. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from that of SBS18. Through an independent analysis of 2,616 whole-genome sequenced microsatellite-stable CRCs across three distinct cohorts, we demonstrate that SBS_D is consistently present at a similar prevalence, suggesting that this signature may have been previously overlooked. Using a naïve decomposition approach, we demonstrate that the pattern of SBS_D better aligns with signatures previously associated with deficiencies in DNA polymerase delta (POLD1) proofreading and mismatch repair. However, multiple lines of evidence, including the absence of pathogenic mutations in the exonuclease domain of POLD1 or in mismatch repair-associated genes, indicate that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in microsatellite-stable CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development in samples without canonical defects in DNA repair pathways.

Journal Article↗