Alaa Siddig

Breast cancer is a heterogeneous disease that claims 670,000 lives by 2022. Omic technologies, particularly next generation sequencing (NGS) offers promising avenues for precision medicine. American Society of Clinical Oncology (ASCO) outlines genomic testing's utility, emphasizing prognostic and diagnostic potential. This review succinctly explores NGS's evolution and clinical applications of NGS in breast cancer, thereby guiding future research to enhance patient care. Comprehensive literature searches were conducted using databases such as PubMed, Google Scholar, and ResearchGate, focusing on keywords including breast cancer, HER-2 low breast cancer, circulating tumour DNA, single-cell RNA sequencing, and next-generation sequencing. Peer-reviewed, high-quality articles published in English were selected for inclusion. Previous studies have explored the evolution of NGS technology and its clinical applications in breast cancer, including genomic and transcriptomic characterization, treatment guidance, and resistance prediction. Molecular profiling of challenging entities such as early-onset breast cancer and HER-2 low tumours was summarized, with key findings highlighted. This review also discusses emerging technologies, including circulating DNA and single-cell sequencing, as promising avenues for discovery. NGS has revealed the genomic and transcriptomic diversity of breast cancer, identifying actionable alterations associated with chemotherapy response and resistance to therapies such as trastuzumab, TKIs, and CDK4/6 inhibitors. Circulating tumour DNA (ctDNA) shows potential for diagnosis, prediction, prognosis, and monitoring, despite tumour heterogeneity. Single-cell analysis enables exploration of individual cell transcriptomes, though high costs and low throughput remain barriers to widespread adoption. HER2-low tumours continue to pose significant research challenges.

Inflammatory Bowel Diseases (IBD), which encompass ulcerative colitis (UC) and Crohn’s disease (CD), are characterized by chronic inflammation and tissue damage of the gastrointestinal tract. This study aimed to uncover novel disease-gene signatures, dysregulated pathways, and the immune cell infiltration landscape of inflamed tissues. Eight publicly available transcriptomic datasets, including inflamed and non-inflamed tissues from CD and UC patients were analyzed. Common differentially expressed genes (DEGs) were identified through meta-analysis, revealing 180 DEGs. DEGs were implicated in leukocyte transendothelial migration, PI3K-Akt, chemokine, NOD-like receptors, TNF signaling pathways, and pathways in cancer. Protein–protein interaction network and cluster analysis identified 14 central IBD players, which were validated using eight external datasets. Disease module construction using the NeDRex platform identified nine out of 14 disease-associated genes (CYBB, RAC2, GNAI2, ITGA4, CYBA, NCF4, CPT1A, NCF2, and PCK1). Immune infiltration profile assessment revealed a significantly higher degree of infiltration of neutrophils, activated dendritic cells, plasma cells, mast cells (resting/activated), B cells (memory/naïve), regulatory T cells, and M0 and M1 macrophages in inflamed IBD tissue. Collectively, this study identified the immune infiltration profile and nine disease-associated genes as potential modulators of IBD pathogenesis, offering insights into disease molecular mechanisms, and highlighting potential disease modulators and immune cell dynamics.

Background: Breast cancer developed at a young age (≤45 years) is hypothesized to have unique biology; however, findings in this field are controversial. Methods: We compared the whole transcriptomic profile of young vs. old-age breast cancer using DNA microarray. RNA was extracted from 13 fresh estrogen receptor (ER)-positive primary breast cancer tissues of untreated patients (7 = young age ≤45 years and 6 = old age ≥55 years). In silico validation for the differentially expressed genes (DEGs) by young-age patients was conducted using The Cancer Genome Atlas (TCGA) database. Next, we analyzed the protein expression encoded by two of the significantly down-regulated genes by young-age patients, Glycine N-acyltransferase-like 1 (GLYATL-1) and Ran-binding protein 3 like (RANBP3L), using immunohistochemical analysis in an independent cohort of 56 and 74 ER-positive pre-therapeutic primary breast cancer tissues, respectively. Results: 12 genes were significantly differentially expressed by young-age breast cancers (fold change >2 or p-value < 0.05). TCGA data confirmed the differential expression of six genes. Protein expression analysis of GLYATL-1 and RANBP3L did not show heterogeneous expression between young and old-age breast cancer tissues. Loss of expression of GLYATL-1 was significantly (p-value 0.005) associated with positive lymph node status. Higher expression of RANBP3L was significantly associated with breast cancers with lower histopathological grades (p-value 0.038). Conclusions: At the transcriptomic level, breast cancer developed in young and old age patients seems homogenous. The variation in the transcriptomic profiles can be attributed to the other clinicopathological characteristics rather than the age of the patient.

Biomarker identification is imperative for invasive breast carcinoma, which is more aggressive and associated with higher mortality and worse prognosis in younger patients (50 years). The current study aimed to investigate angiopoietin-like protein 4 (ANGPTL4) and insulin-like growth factor-1 (IGF-1) protein expression in breast tissue from young patients with breast carcinoma. Immunohistochemical staining was applied in formalin-fixed, paraffin-embedded samples of breast carcinoma tissue from young patients aged p = 0.897) and IGF-1 (p = 0.091) expression and molecular subtypes of breast carcinoma. The histological grade was a significant predictor of ANGPTL4 expression (grade 1 vs. grade 3, adjusted odds ratio = 12.39, p = 0.040). Therefore, ANGPTL-4 and IGF-1 expressions are common in young breast carcinoma tissue. There is a potential use of them as biomarkers in breast carcinoma.

Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients.