Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms.

JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.

Multiomic analysis of HER2-enriched and AR-positive breast carcinoma with apocrine differentiation and an oligometastatic course: a case report.

Breast carcinoma is the most prevalent cancer among women globally. It has variable clinical courses depending on the stage and clinical-biological features. This case report describes a 56-year-old female with invasive breast cancer without estrogen or progesterone receptor expression, with apocrine differentiation, and with no germline variants in the BRCA1 and BRCA2 genes. Throughout the clinical course, the patient exhibited discordant results for HER2 in immunohistochemistry and in situ hybridization. During the second relapse, the disease displayed apocrine microscopic features. The tumor underwent analysis for the androgen receptor, GCDFP-15, RNA-seq, and whole-genome sequencing (WGS) to identify the breast cancer subtype and to characterize the cancer genome. Our bioinformatic analysis revealed 20,323 somatic SNV/Indels, including five mutations in cancer-related genes that are believed to be responsible for the tumor's development. Two of these mutations were found in the PIK3CA and TP53 genes. Furthermore, the tumor tissue exhibited large copy number alterations to the chromosomes, which could impact gene expression through complex mechanisms and contribute to the tumor phenotype. Clustering algorithms applied on RNA-sequencing data categorized this cancer as a HER2+ subtype. The second-line capecitabine chemotherapy treatment is ongoing, and the patient is responding well. Bioinformatic results support the current treatment decision and open the way to further treatments.