Link between steroidogenesis, the cell cycle, and PKA in adrenocortical tumor cells

International audienceAdrenocortical tumors (ACTs) frequently cause steroid excess and present cell-cycle dysregulation. cAMP/PKA signaling is involved in steroid synthesis and play a role in cell-cycle regulation. We investigated, by cell synchronization in the different phases of the cell-cycle, the control of steroidogenesis and the contribution of PKA in adrenocortical cells (H295R and culture of primary pigmented nodular adrenocortical disease cells). Cells showed increased steroidogenesis and a maximal PKA activity at G2 phase, and a reduction at G1 phase. PRKACA overexpression, or cAMP stimulation, enhanced PKA activity and induced steroidogenesis in all synchronized groups but is not sufficient to drive cell-cycle progression. PRKAR1A inactivation enhanced PKA activity and induced STAR gene expression, only in cells in G1, and triggered cell-cycle progression in all groups.These findings provide evidence for a tight association between steroidogenesis and cell-cycle in ACTs. Moreover, PRKAR1A is essential for mediating the function of PKA activity on both steroidogenesis and cell-cycle progression in adrenocortical cells

Rational testing for gene fusion in colorectal cancer: MSI and RAS-BRAF wild-type metastatic colorectal cancer as target population for systematic screening

International audienceGene fusions provide access to new therapeutic opportunities for patients treated for a colorectal cancer (CRC). However, they do not excess 1% of patients. A better identification of patients in whom gene fusions are highly prevalent is a major issue in a therapeutic and medico-economics perspective. This study assesses the rates of gene fusions in CRC patients with MSI/RAS-BRAFWT in our routine practice detected with a commercially available NGS-based fusion panel. Among the 130 MSI CRC tumors, 43 (33%) were KRAS-NRAS-BRAFWT. A gene fusion was detected in 7 (25.9%) of the 27 MSI/RAS-BRAFWT samples, which had RNA suitable for analysis after quality control. These fusions involved mainly NTRK1/3 (n = 5), as well as ALK (n = 1) and BRAF (n = 1). In the present study, we confirm that patients with MSI/RAS-BRAFWT CRCs represent a subpopulation in which targetable gene fusions are overrepresented. Our results support the use of a two-step algorithm for molecular screening, in which metastatic CRC patients would have routine MSI and RAS/BRAF testing, and then only those with MSI/RAS-BRAFWT would be screened with dedicated NGS RNA panel for gene fusions

HORMAD1 overexpression predicts response to anthracycline–cyclophosphamide and survival in triple‐negative breast cancers

Triple negative breast cancers (TNBCs) represent 15–20% of all breast cancers and are associated with higher recurrence and distant metastasis rate. Standard of care for early stage TNBC is anthracyclines combined with cyclophosphamide (AC) followed by taxanes, in the neo‐adjuvant or adjuvant setting. This work aimed to identify predictive biomarkers of AC response in patient‐derived xenograft (PDX) models of TNBC and to validate them in the clinical setting. By gene and protein expression analysis of 39 PDX with different responses to AC, we found that high expression of HORMAD1 was associated with better response to AC. Both gene and protein expression were associated with promoter hypomethylation. In a cohort of 526 breast cancer patients, HORMAD1 was overexpressed in 71% of TNBC. In a second cohort of 186 TNBC patients treated with AC, HORMAD1 expression was associated with longer metastasis‐free survival (MFS). In summary, HORMAD1 overexpression was predictive of an improved response to AC in PDX and is an independent prognostic factor in TNBC patients treated with AC

Male breast cancer: No evidence for mosaic BRCA1 promoter methylation involvement

Breast cancers (BC) are rare in men and are often caused by constitutional predisposing factors. In women, mosaic BRCA1 promoter methylations (MBPM) are frequent events, detected in 4–8% of healthy subjects. This constitutional epimutation increases risk of early-onset and triple-negative BC. However, the role of MBPM in male BC predisposition has never been assessed. We screened 40 blood samples from men affected by BC, and performed extensive tumour analysis on MBPM-positive patients. We detected two patients carrying MBPM. Surprisingly, tumour analysis revealed that neither of these two male BCs were caused by the constitutional BRCA1 epimutations carried by the patients

Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma

International audienceA prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture-HPV method followed by next-generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV-chromosomal junctions colinear (2J-COL) or nonlinear (2J-NL), multiple hybrid junctions clustering in a single chromosomal region (MJ-CL) or scattered over different chromosomal regions (MJ-SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV-human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers

Homologous recombination deficiency is linked with platinum-based chemotherapy response in triple-negative breast cancer (TNBC) but methods to clinically identify these patients are lacking. Here, using patient-derived xenografts of TNBC the authors demonstrate that shallow HRD is predictive of response to platinum-based chemotherapy