NUT carcinoma of the submandibular gland: A case report.

BACKGROUND: NUT carcinoma (NUTc) is a rare and aggressive malignant epithelial tumor characterized by rearrangement of the NUT gene on chromosome 15q14. METHODS: In this article, we present the fifth case worldwide of a young woman affected by a NUTc arising from a submandibular gland, presenting as a rapidly evolving mass. She underwent a right scialoadenectomy and received the initial diagnosis of high-grade mucoepidermoid carcinoma. Due to evidence of local recurrence at magnetic resonance imaging 1 month later, a subsequent right radical neck dissection was performed. The patient then sought a second opinion at our cancer center and finally received the correct diagnosis of NUT carcinoma. Given the well-known aggressive behavior of this neoplasm, as well as clinical and radiological features, she underwent adjuvant chemo-radiation (intensity-modulated radiotherapy + concurrent chemotherapy with cisplatin). RESULTS: After a disease-free interval of 2.6 months, a widespread metastatic disease led to rapid deterioration of performance status and patient death in a few weeks after metastatic onset. CONCLUSIONS: We presented a case of NUTc arising from salivary gland aiming to improve the knowledge of this rare malignancy. First, we pointed out that in the setting of rare tumors like salivary gland cancers, the diagnosis should be obtained by expert pathologists, and patients should be referred to tertiary cancer centers for their clinical management. Second, molecular profiling may help to identify possible druggable targets that may be exploited to treat patients suffering from this aggressive malignancy. Sharing the molecular data provided in this case will be useful for further research.

ESR1 gene amplification and MAP3K mutations are selected during adjuvant endocrine therapies in relapsing Hormone Receptor-positive, HER2-negative breast cancer (HR+ HER2- BC).

BACKGROUND: Previous studies have provided a comprehensive picture of genomic alterations in primary and metastatic Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer (HR+ HER2- BC). However, the evolution of the genomic landscape of HR+ HER2- BC during adjuvant endocrine therapies (ETs) remains poorly investigated. METHODS AND FINDINGS: We performed a genomic characterization of surgically resected HR+ HER2- BC patients relapsing during or at the completion of adjuvant ET. Using a customized panel, we comprehensively evaluated gene mutations and copy number variation (CNV) in paired primary and metastatic specimens. After retrieval and quality/quantity check of tumor specimens from an original cohort of 204 cases, 74 matched tumor samples were successfully evaluated for DNA mutations and CNV analysis. Along with previously reported genomic alterations, including PIK3CA, TP53, CDH1, GATA3 and ESR1 mutations/deletions, we found that ESR1 gene amplification (confirmed by FISH) and MAP3K mutations were enriched in metastatic lesions as compared to matched primary tumors. These alterations were exclusively found in patients treated with adjuvant aromatase inhibitors or LHRH analogs plus tamoxifen, but not in patients treated with tamoxifen alone. Patients with tumors bearing MAP3K mutations in metastatic lesions had significantly worse distant relapse-free survival (hazard ratio [HR] 3.4, 95% CI 1.52-7.70, p value 0.003) and worse overall survival (HR 5.2, 95% CI 2.10-12.8, p-value < 0.001) independently of other clinically relevant patient- and tumor-related variables. CONCLUSIONS: ESR1 amplification and activating MAP3K mutations are potential drivers of acquired resistance to adjuvant ETs employing estrogen deprivation in HR+ HER2- BC. MAP3K mutations are associated with worse prognosis in patients with metastatic disease.

Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network.

BACKGROUND: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. METHODS: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. RESULTS: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. CONCLUSIONS: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.

Corrigendum: Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group.

[This corrects the article DOI: 10.3389/fonc.2020.00489.].

Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group.

This work describes the set-up of a shared platform among the laboratories of the Alleanza Contro il Cancro (ACC) Italian Research Network for the identification of fusion transcripts in sarcomas by using Next Generation Sequencing (NGS). Different NGS approaches, including anchored multiplex PCR and hybrid capture-based panels, were employed to profile a large set of sarcomas of different histotypes. The analysis confirmed the reliability of NGS RNA-based approaches in detecting sarcoma-specific rearrangements. Overall, the anchored multiplex PCR assay proved to be a fast and easy-to-analyze approach for routine diagnostics laboratories.

Gastroblastoma in Adulthood-A Rarity among Rare Cancers-A Case Report and Review of the Literature.

Gastroblastoma (GB) is a rare gastric epithelial-mesenchymal neoplasm, first described by Miettinen et al. So far, all reported cases described the tumor in children or young adults, and similarities with other childhood blastomas have been postulated. We report a case of GB in a 43-year-old patient with long follow up and no recurrence up to 100 months after surgery. So far, this is the second case of GB occurring in the adult age >40-year-old. Hence, GB should be considered in the differential diagnosis of microscopically comparable conditions in adults carrying a worse prognosis and different clinical approach.

The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1 (EWSR1)-Wilm's tumor suppressor (WT1) translocation. We used whole-exome sequencing to interrogate six consecutive pre-treated DSRCTs whose gene expression was previously investigated. METHODS: DNA libraries were prepared from formalin-fixed, paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows-Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software. RESULTS: A total of 137 unique somatic mutations were identified: 133 mutated genes were case-specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage-response (DDR) network that was also identified through IPA and mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA. Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded. CONCLUSIONS: The emerging picture is an extreme inter-tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.

Self-Assembled Nanomicelles as Curcumin Drug Delivery Vehicles: Impact on Solitary Fibrous Tumor Cell Protein Expression and Viability.

Solitary fibrous tumors (SFTs) are rare soft tissue sarcomas that rely on several epithelial-mesenchymal transition (EMT) protein regulators for invasion/metastatic progression. Curcumin (CUR) has several pharmacological activities, including anticancer activity and the ability to suppress the EMT process. However, poor absorption, rapid metabolism, and side effects at high doses limit the clinical applications of CUR. Here we present the results obtained by treating SFT cells with free CUR and three different CUR-loaded nanomicelles (NMs), each of which has its surface decorated with different ligands. All CUR-loaded NMs were more efficient in suppressing SFT cell viability and expression of EMT markers than CUR alone. Combined treatments with the pan-histone deacetylase dual inhibitor SAHA revealed a differential ability in inhibiting EMT markers expression and SFT cell invasiveness, depending on the NM-ligand type. Finally, combinations of photodynamic therapy and CUR-loaded NM administrations resulted in almost complete SFT cell viability abrogation 24 h after laser irradiation.

Response to isolated limb perfusion and chemotherapy with epirubicin plus ifosfamide in a metastatic malignant ossifying fibromyxoid tumor.

BACKGROUND: Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain lineage and intermediate biological potential. It is more common in middle-aged men, usually arising from the deep tissues of the extremities. It is now established that it is a translocation related tumor, most often marked by translocation of PHF1 gene. Surgery is the mainstay of treatment and proves usually curative, although, in rarer cases the disease shows malignant features and tendency to recur both locally and at distant sites. In such cases, no standard treatment exists. CASE PRESENTATION: We report on a case of malignant advanced OFMT of the hand with lung metastases responding to isolated limb perfusion with human recombinant tumor necrosis factor and melphalan and chemotherapy with epirubicin and ifosfamide. CONCLUSIONS: To our knowledge, this is the first report of activity of soft tissue sarcoma-oriented chemotherapy in advanced OFMT.

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases.

The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.

Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database.

BACKGROUND: The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network ("Rete Tumori Rari"; RTR). METHODS: We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15-20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RESULTS: Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic; WWTR1 rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1-45), with four patients progression-free at 24 months. The clinical benefit (complete response [CR] + PR + SD >6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1-8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients. CONCLUSIONS: A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.

Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptor-positive salivary gland cancers.

BACKGROUND: Androgen deprivation therapy has some clinical activity in selected salivary gland cancer histotypes, with androgen receptor expression. METHODS: We retrospectively analyzed patients with androgen receptor-expressing recurrent/metastatic salivary gland cancer, treated with androgen deprivation therapy. Protein expression of androgen receptor and ErbB family members was investigated. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. RESULTS: Seventeen patients were identified. No significant toxicities were reported. Overall response rate was 64.7%; 3-year PFS and 5-year OS were 11.8% and 19.3%, respectively. Androgen receptor overexpression may be sustained by gain of chromosome X (58%) and TP53 mutation (44%). No association between response to androgen deprivation therapy and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, HER3 expression, PIK3CA mutations, or phosphatase and tensin homolog (PTEN) deletion was identified. CONCLUSION: We confirm the activity of androgen deprivation therapy in androgen receptor-expressing recurrent/metastatic salivary gland cancers. The hypothesis that an androgen receptor increased gene copy number may represent a possible mechanism of primary resistance should be further investigated.

Myogenic differentiation and histologic grading are major prognostic determinants in retroperitoneal liposarcoma.

The aim of the present work was to improve the understanding of the impact of malignancy grade and myogenic/rhabdomyoblastic differentiation on the natural course of retroperitoneal liposarcoma. All consecutive patients affected by primary well-differentiated (WD)/dedifferentiated (DD) retroperitoneal liposarcoma, surgically treated at our institution between January 2002 and December 2011, were retrospectively evaluated. Tumors were stained for mdm2 and 5 myogenic markers (smooth muscle actin-α, h-caldesmon, calponin, desmin, myogenin). The French National Federation of the Centers for the Fight Against Cancer (FNCLCC) grading system was applied. Overall survival, crude cumulative incidence of local recurrence, and distant metastases were calculated. Multivariable analyses were carried out. A total of 144 patients were identified. Median follow-up was 68 months (interquartile range: 46 to 104 mo). Fifty-two patients were affected by WD/G1 and 92 by DD liposarcoma. Among the latter, 60 were grade G2 and 32 G3. Myogenic differentiation was present in 54 cases (8/52 WD/G1, 27/60 DD/G2, 18/32 DD/G3). Seven cases had a rhabdomyoblastic DD component (1/60 DD/G2 and 6/32 DD/G3). Five-year overall survival rates were 93%, 57%, and 21% for WD/G1 liposarcoma, G2 DD, and G3 DD liposarcoma, respectively, and 75%, 42%, and 29% for liposarcoma without myogenic differentiation, with myogenic differentiation, with rhabdomyoblastic differentiation, respectively (P<0.001). Of note, 5/6 patients affected by G3 DD liposarcoma with a rhabdomyoblastic component died within 8 months. FNCLCC grade and myogenic differentiation significantly predicted the outcome of retroperitoneal liposarcoma. These should be factored into treatment decision-making and possibly used to stratify patients in clinical trials.

Identification of a gene expression driven progression pathway in myxoid liposarcoma.

AIM: to investigate the events involved in the progression of myxoid liposarcoma (MLS). Gene expression profiling and immunohistochemical/biochemical analyses were applied to specimens representative of the opposite ends of the MLS spectrum: pure myxoid (ML) and pure round cell (RC) liposarcomas. The analyses revealed the involvement of both coding and non coding RNAs (SNORDs located in DLK1-DIO3 region) and support a model of stepwise progression mainly driven by epigenetic changes involving tumour vascular supply and tumoral cellular component. In this model, a switch in the vascular landscape from a normal to a pro-angiogenic signature and the silencing of DLK1-DIO3 region mark the progression from ML to RC in concert with the acquisition by the latter of the over-expression of YYI/C-MYC/HDAC2, together with over-expression of genes involved in cell proliferation and stemness: MKNK2, MSX1 and TRIM71. Taken together, these findings strongly suggest that to progress from ML to RC liposarcoma the cells have to overcome the epigenetic silencing restriction point in order to reset their new stem-like differentiation signature. Our findings provide a first attempt at identifying the missing links between ML and RC liposarcomas, that may also have broader applications in other clinico-pathological settings characterised by a spectrum of progression.

Development of transplantable human chordoma xenograft for preclinical assessment of novel therapeutic strategies.

BACKGROUND: Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies. METHODS: In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor. RESULTS: All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and post treatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors. CONCLUSIONS: Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies.

The clinical impact and molecular biology of del(17p) in multiple myeloma treated with conventional or thalidomide-based therapy.

Hemizygous deletion of 17p (del(17p)) has been identified as a variable associated with poor prognosis in myeloma, although its impact in the context of thalidomide therapy is not well described. The clinical outcome of 85 myeloma patients with del(17p) treated in a clinical trial incorporating both conventional and thalidomide-based induction therapies was examined. The clinical impact of deletion, low expression, and mutation of TP53 was also determined. Patients with del(17p) did not have inferior response rates compared to patients without del(17p), but, despite this, del(17p) was associated with impaired overall survival (OS) (median OS 26.6 vs. 48.5 months, P < 0.001). Within the del(17p) group, thalidomide induction therapy was associated with improved response rates compared to conventional therapy, but there was no impact on OS. Thalidomide maintenance was associated with impaired OS, although our analysis suggests that this effect may have been due to confounding variables. A minimally deleted region on 17p13.1 involving 17 genes was identified, of which only TP53 and SAT2 were underexpressed. TP53 was mutated in <1% in patients without del(17p) and in 27% of patients with del(17p). The higher TP53 mutation rate in samples with del(17p) suggests a role for TP53 in these clinical outcomes. In conclusion, del(17p) defined a patient group associated with short survival in myeloma, and although thalidomide induction therapy was associated with improved response rates, it did not impact OS, suggesting that alternative therapeutic strategies are required for this group.

Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival.

PURPOSE: Regions on 1p with recurrent deletions in presenting myeloma patients were examined with the purpose of defining the deletions and assessing their survival impact. EXPERIMENTAL DESIGN: Gene mapping, gene expression, FISH, and mutation analyses were conducted on patient samples from the MRC Myeloma IX trial and correlated with clinical outcome data. RESULTS: 1p32.3 was deleted in 11% of cases, and deletion was strongly associated with impaired overall survival (OS) in patients treated with autologous stem cell transplant (ASCT). In patients treated less intensively, del(1)(p32.3) was not associated with adverse progression-free survival (PFS) or OS. The target of homozygous deletions was CDKN2C, however its role in the adverse outcome of cases with hemizygous deletion was less certain. 1p22.1-21.2 was the most frequently deleted region and contained the candidate genes MTF2 and TMED5. No mutations were identified in these genes. 1p12 was deleted in 19% of cases, and deletion was associated with impaired OS in univariate analysis. The target of homozygous deletion was FAM46C, which was mutated in 3.4% of cases. When cases with FAM46C deletion or mutation were considered together, they were strongly associated with impaired OS in the intensive treatment setting. CONCLUSION: Deletion of 1p32.3 and 1p12 was associated with impaired OS in myeloma patients receiving ASCT. FAM46C was identified as a gene with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations.

Gender disparities in the tumor genetics and clinical outcome of multiple myeloma.

BACKGROUND: Several cancer types have differences in incidence and clinical outcome dependent on gender, but these are not well described in myeloma. The aim of this study was to characterize gender disparities in myeloma. METHODS: We investigated the association of gender with the prevalence of tumor genetic lesions and the clinical outcome of 1,960 patients enrolled in the phase III clinical trial MRC Myeloma IX. Genetic lesions were characterized by FISH. RESULTS: Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001) and hyperdiploidy being more common in men (50% female vs. 62% male, P < 0.001). There were also differences in secondary genetic events with del(13q) (52% female vs. 41% male, P < 0.001) and +1q (43% female vs. 36% male, P = 0.042) being found more frequently in female myeloma patients. Female gender was associated with inferior overall survival (median: 44.8 months female vs. 49.9 months male, P = 0.020). CONCLUSIONS: We found gender-dependent differences in the prevalence of the primary genetic events of myeloma, with IGH translocations being more common in women and hyperdiploidy more common in men. This genetic background may impact subsequent genetic events such as +1q and del(13q), which were both more frequent in women. The higher prevalence of lesions associated with poor prognosis in the female myeloma population, such as t(4;14), t(14;16) and +1q, may adversely affect clinical outcome. IMPACT: These differences suggest that gender influences the primary genetic events of myeloma.

The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gammopathies of undetermined significance.

A large series of plasma cell dyscrasias (n=2207) was examined for translocations which deregulate the MAF genes, t(14;20)(q32;q12) and t(14;16)(q32;q23), and their disease behavior was compared to a group characterized by the t(4;14)(p16;q32) where CCND2 is also up-regulated. The t(14;20) showed low prevalence in myeloma (27/1830, 1.5%) and smoldering myeloma (1/148, <1%) with a higher incidence in MGUS (9/193, 5% P=0.005). Strong associations with del(13) (76%), non-hyperdiploidy (83%) and gain of 1q (58%) were seen but no association with an IgA M-protein or absence of bone disease was noted. All three translocations were associated with poor outcome in myeloma, but strikingly all t(14;20) MGUS/smoldering myeloma cases (n=10) had stable, low level disease. In contrast, the 10 t(14;16) and 25 t(4;14) MGUS/smoldering myeloma cases were associated with both evolving and non-evolving disease. None of the associated genetic abnormalities helped to predict for progression from MGUS or smoldering myeloma.