ABSTRACT
Germline mutations in BRCA1-associated protein 1 (BAP1) are associated with several neoplasms, including BAP1-inactivated melanocytic tumors (BIMTs). BIMTs are classically described as biphenotypic melanocytic proliferations with BAP1-deficient large epithelioid and rhabdoid melanocytes showing various degrees of cytologic atypia. This morphology has been traditionally classified as "spitzoid" despite the various differences between these lesions and the more classic Spitz nevi. Herein, we report a case of an otherwise healthy 11-year-old female patient with a family history of several malignancies who presented with multiple pink to brown papules. Histologic and immunohistochemical evaluation identified three lesions with loss of nuclear BAP1 staining. The histologic spectrum of these lesions included junctional spitzoid cells within a triphenotypic proliferation and a separate lesion composed entirely of dermal small to medium-sized epithelioid melanocytes with maturation. BAP1 gene sequencing revealed a germline frameshift pathogenic BAP1 mutation, denoted c.1717delC. This case provides further evidence that not all BIMTs conform to classic morphological criteria and that the morphologic spectrum includes lesions resembling conventional nevi. As BIMTs can serve as an early marker of the BAP1 hereditary tumor predisposition syndrome, we believe a need exists for a more comprehensive combined clinical and pathological approach for BIMT identification.
Subject(s)
Germ-Line Mutation , Melanocytes , Neoplastic Syndromes, Hereditary , Nevus, Epithelioid and Spindle Cell , Skin Neoplasms , Tumor Suppressor Proteins , Ubiquitin Thiolesterase , Child , Female , Humans , Melanocytes/metabolism , Melanocytes/pathology , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Neoplastic Syndromes, Hereditary/pathology , Nevus, Epithelioid and Spindle Cell/genetics , Nevus, Epithelioid and Spindle Cell/metabolism , Nevus, Epithelioid and Spindle Cell/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolismABSTRACT
Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.
Subject(s)
Albumins/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Deoxycytidine/analogs & derivatives , Hyaluronoglucosaminidase/metabolism , Paclitaxel/administration & dosage , Pancreatic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/secondary , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Enoxaparin/administration & dosage , Female , Fibrinolytic Agents/administration & dosage , Humans , Hyaluronic Acid/metabolism , Hyaluronoglucosaminidase/administration & dosage , Male , Middle Aged , Paclitaxel/adverse effects , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Progression-Free Survival , Thromboembolism/chemically induced , Thromboembolism/prevention & control , Time Factors , GemcitabineABSTRACT
Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.
Subject(s)
Amino Acid Transport System ASC/metabolism , Amino Acid Transport System A/metabolism , Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , DNA-Binding Proteins/physiology , Endoplasmic Reticulum Stress/drug effects , Paclitaxel/pharmacology , Ubiquitin-Protein Ligases/physiology , Amino Acid Transport System A/genetics , Amino Acid Transport System ASC/genetics , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Autophagy/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Citric Acid Cycle/drug effects , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum Stress/genetics , Female , Humans , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Minor Histocompatibility Antigens , Paclitaxel/therapeutic use , Proteolysis/drug effects , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , UbiquitinationABSTRACT
AIMS: HER2NEU gene amplification is present in the majority of invasive breast carcinomas that have HER2 protein overexpression. A subset of breast cancers harbour an increased chromosome 17 (CEP17) copy number (polysomy 17). We investigated the clinicopathologic significance of polysomy 17 in correlation with various histological parameters and HER2NEU gene amplification. METHODS: We collected the surgical specimens of 266 consecutive cases of primary invasive breast carcinomas. HER2NEU gene status and CEP17 copy numbers were assessed by fluorescent in situ hybridisation (FISH). Chromosome 17 polysomy was determined by the presence of ≥3 average CEP17 signals per nucleus. RESULTS: 63 tumours (23.7%) harboured polysomy 17. Carcinomas with polysomy 17 were associated with adverse histological indicators including high histological grade, high nuclear grade, poor Nottingham Prognostic Index, advanced local tumour extent and progesterone receptor negativity. Polysomy 17 was common to HER2NEU amplified and unamplified tumours, and more frequently observed in HER2NEU unamplified (71.4%) cases. CONCLUSIONS: In the absence of the gene amplification, HER2 protein overexpression may be explained by other mechanisms including polysomy 17.