Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

The Transcriptomic Landscape of Age-Induced Changes in Human Visceral Fat and the Predicted Omentum-Liver Connectome in Males.

Aging causes alterations in body composition. Specifically, visceral fat mass increases with age and is associated with age-related diseases. The pathogenic potential of visceral fat accumulation has been associated with its anatomical location and metabolic activity. Visceral fat may control systemic metabolism by secreting molecules that act in distal tissues, mainly the liver, through the portal vein. Currently, little is known about age-related changes in visceral fat in humans. Aiming to identify molecular and cellular changes occurring with aging in the visceral fat of humans, we analyzed publicly available transcriptomic data of 355 omentum samples from the Genotype-Tissue Expression portal (GTEx) of 20-79-year-old males and females. We identified the functional enrichment of genes associated with aging, inferred age-related changes in visceral fat cellularity by deconvolution analysis, profiled the senescence-associated secretory phenotype of visceral adipose tissue, and predicted the connectivity of the age-induced visceral fat secretome with the liver. We demonstrate that age induces alterations in visceral fat cellularity, synchronous to changes in metabolic pathways and a shift toward a pro-inflammatory secretory phenotype. Furthermore, our approach identified candidates such as ADIPOQ-ADIPOR1/ADIPOR2, FCN2-LPR1, and TF-TFR2 to mediate visceral fat-liver crosstalk in the context of aging. These findings cast light on how alterations in visceral fat with aging contribute to liver dysfunction and age-related disease etiology.

Interplay Between Immune and Cancer-Associated Fibroblasts: A Path to Target Metalloproteinases in Penile Cancer.

Extracellular matrix (ECM) remodeling and inflammation have been reported in penile carcinomas (PeCa). However, the cell types and cellular crosstalk involved in PeCa are unexplored. We aimed to characterize the complexity of cells and pathways involved in the tumor microenvironment (TME) in PeCa and propose target molecules associated with the TME. We first investigated the prognostic impact of cell types with a secretory profile to identify drug targets that modulate TME-enriched cells. The secretome analysis using the PeCa transcriptome revealed the enrichment of inflammation and extracellular matrix pathways. Twenty-three secreted factors were upregulated, mainly collagens and matrix metalloproteinases (MMPs). The deregulation of collagens and MMPs was confirmed by Quantitative reverse transcription - polymerase chain reaction (RT-qPCR). Further, the deconvolution method (digital cytometry) of the bulk samples revealed a high proportion of macrophages and dendritic cells (DCs) and B cells. Increased DCs and B cells were associated with better survival. A high proportion of cancer-associated fibroblasts (CAFs) was observed in low-survival patients. Patients with increased CAFs had decreased immune cell proportions. The treatment with the MMP inhibitor GM6001 in CAF cells derived from PeCa resulted in altered cell viability. We reported a crosstalk between immune cells and CAFs, and the proportion of these cell populations was associated with prognosis. We demonstrate that a drug targeting MMPs modulates CAFs, expanding the therapeutic options of PeCa.