Multiple primary malignances managed with surgical excision: a case report with next generation sequencing analysis.

BACKGROUND: Multiple primary malignancies (MPM) are defined as tumors originating in the same individual without any correlation between them. In addition to morphological and immunohistochemical analyses, sensitive DNA sequencing methods such as next generation sequencing (NGS) may help to discriminate the common or different genetic alterations driving each malignancy, to better diagnose these uncommon cases. METHODS AND RESULTS: Here we report the case of a man who developed a poorly differentiated gastric adenocarcinoma invading the pancreas followed, two years later, by a colorectal cancer involving also the kidney and the diaphragm. Despite the advanced stage of both diseases, adjuvant chemotherapy was successful. While the second tumor was initially interpreted as a relapse of his stomach cancer, NGS-based mutation profiling of the two carcinomas revealed two distinct malignances, independently developing in different times and indicative of metachronous MPM. Indeed, sequencing of cancer-associated genes identified somatic mutations only in the first gastric cancer, besides germline variants on three different genes (PDGFRA, APC and TP53). However, analysis of both somatic and germline mutations with bio-informatics prediction tools failed to find a correlation between these variants and the unexpectedly good prognosis of both cancers. CONCLUSIONS: In summary, NGS analysis contributed to defined different molecular profiles for two tumors developed in the span of two years, thus allowing diagnosing the case as MPN. However, NGS was unable to establish a direct correlation between the identified alterations and cancer development.

Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes.

Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES). Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. With the advent of molecular genetic analyses, such as T-cell receptor gene rearrangement assays and Next Generation Sequencing, it is possible to better characterize these syndromes and establish which patients will benefit from pharmacological targeted therapy. In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials.

Opportunities and Challenges of Liquid Biopsy in Thyroid Cancer.

Thyroid cancer is the most common malignancy of the endocrine system, encompassing different entities with distinct histological features and clinical behavior. The diagnostic definition, therapeutic approach, and follow-up of thyroid cancers display some controversial aspects that represent unmet medical needs. Liquid biopsy is a non-invasive approach that detects and analyzes biological samples released from the tumor into the bloodstream. With the use of different technologies, tumor cells, free nucleic acids, and extracellular vesicles can be retrieved in the serum of cancer patients and valuable molecular information can be obtained. Recently, a growing body of evidence is accumulating concerning the use of liquid biopsy in thyroid cancer, as it can be exploited to define a patient's diagnosis, estimate their prognosis, and monitor tumor recurrence or treatment response. Indeed, liquid biopsy can be a valuable tool to overcome the limits of conventional management of thyroid malignancies. In this review, we summarize currently available data about liquid biopsy in differentiated, poorly differentiated/anaplastic, and medullary thyroid cancer, focusing on circulating tumor cells, circulating free nucleic acids, and extracellular vesicles.

Delayed use of eribulin in a heavily pretreated liposarcoma patient, previously misdiagnosed as leiomyosarcoma.

Due to its low incidence, liposarcoma displays a limited number of therapeutic options. However, eribulin recently received approval for the treatment of advanced liposarcoma patients, progressing to at least two chemotherapy lines. We report herein the case of a man initially diagnosed with a leyomiosarcoma, subsequently reclassified as a dedifferentiated liposarcoma, who received eribulin after he failed several therapy lines. Eribulin provided our patient an 8-month disease control and a substantial clinical benefit with no relevant adverse effects, showing a good efficacy and safety profile despite its delayed employ. Additionally, this case strengthens the pivotal importance of molecular profiling in the management of soft tissue sarcomas.

Colony-Forming Cell Assay Detecting the Co-Expression of JAK2V617F and BCR-ABL1 in the Same Clone: A Case Report.

BCR-ABL1-negative myeloproliferative disorders and chronic myeloid leukaemia are haematologic malignancies characterised by single and mutually exclusive genetic alterations. Nevertheless, several patients co-expressing the JAK2V617F mutation and the BCR-ABL1 transcript have been described in the literature. We report the case of a 61-year-old male who presented with an essential thrombocythaemia phenotype and had a subsequent diagnosis of chronic phase chronic myeloid leukaemia. Colony-forming assays demonstrated the coexistence of 2 different haematopoietic clones: one was positive for the JAK2V617F mutation and the other co-expressed both JAK2V617F and the BCR-ABL1 fusion gene. No colonies displayed the BCR-ABL1 transcript alone. These findings indicate that the JAK2V617F mutation was the founding genetic alteration of the disease, followed by the acquisition of the BCR-ABL1 chimeric oncogene. Our data support the hypothesis that a heterozygous JAK2V617F clone may have favoured the bi-clonal nature of this myeloproliferative disorder, generating clones harbouring a second transforming genetic event.

Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment.

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)-comprising papillary (PTC) and follicular (FTC) tumors-respond to radioiodine therapy, while undifferentiated tumors-including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)-are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Non ABL-directed inhibitors as alternative treatment strategies for chronic myeloid leukemia.

The introduction of ABL Tyrosine Kinase Inhibitors (TKIs) has significantly improved the outcome of Chronic Myeloid Leukemia (CML) patients that, in large part, achieve satisfactory hematological, cytogenetic and molecular remissions. However, approximately 15-20% fail to obtain optimal responses according to the current European Leukemia Network recommendation because of drug intolerance or resistance.Moreover, a plethora of evidence suggests that Leukemic Stem Cells (LSCs) show BCR-ABL1-independent survival. Hence, they are unresponsive to TKIs, leading to disease relapse if pharmacological treatment is discontinued.All together, these biological events generate a subpopulation of CML patients in need of alternative therapeutic strategies to overcome TKI resistance or to eradicate LSCs in order to allow cure of the disease.In this review we update the role of "non ABL-directed inhibitors" targeting signaling pathways downstream of the BCR-ABL1 oncoprotein and describe immunological approaches activating specific T cell responses against CML cells.

New Insights in Thyroid Cancer and p53 Family Proteins.

Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease.

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein.

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABL(I360T) revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.

Biomarkers and prognostic factors for malignant pleural mesothelioma.

The increasing incidence and the dismal prognosis of malignant pleural mesothelioma calls for the identification of biomarkers that will allow a timely diagnosis; display prognostic value; and, predict the response to pharmacological agents employed for the treatment of the disease. Biomarkers associated with early diagnosis currently include mesothelin in combination with miRNA miR-103a-3p. As for prognostic biomarkers, the Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) scores take into account different hematological and clinical parameters that distinguish patients with good prognosis from those with inferior outcomes. Fluorodeoxyglucose-PET, microarray expression data, neutrophil-to-lymphocyte ratios, c-MET expression, Ki-67 ratios and fibulin-3 levels have also been associated with disease outcome. Finally, thymidylate synthase protein cutoffs may predict mesothelioma response to the association of pemetrexed with a platinum derivative.

IRF5 is a target of BCR-ABL kinase activity and reduces CML cell proliferation.

Interferon regulatory factor 5 (IRF5) modulates the expression of genes controlling cell growth and apoptosis. Previous findings have suggested a lack of IRF5 transcripts in both acute and chronic leukemias. However, to date, IRF5 expression and function have not been investigated in chronic myeloid leukemia (CML). We report that IRF5 is expressed in CML cells, where it interacts with the BCR-ABL kinase that modulates its expression and induces its tyrosine phosphorylation. Tyrosine-phosphorylated IRF5 displayed reduced transcriptional activity that was partially restored by imatinib mesylate (IM). Interestingly, a mutant devoid of a BCR-ABL consensus site (IRF5(Y104F)) still presented significant tyrosine phosphorylation. This finding suggests that the oncoprotein phosphorylates additional tyrosine residues or induces downstream signaling pathways leading to further IRF5 phosphorylation. We also found that ectopic expression of IRF5 decreases the proliferation of CML cell lines by slowing their S-G2 transition, increasing the inhibition of BCR-ABL signaling and enhancing the lethality effect observed after treatment with IM, α-2-interferon and a DNA-damaging agent. Furthermore, IRF5 overexpression successfully reduced the clonogenic ability of CML CD34-positive progenitors before and after exposure to the above-indicated cytotoxic stimuli. Our data identify IRF5 as a downstream target of the BCR-ABL kinase, suggesting that its biological inactivation contributes to leukemic transformation.

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy.

In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody-drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.

Single-Cell Analysis in the Omics Era: Technologies and Applications in Cancer.

Cancer molecular profiling obtained with conventional bulk sequencing describes average alterations obtained from the entire cellular population analyzed. In the era of precision medicine, this approach is unable to track tumor heterogeneity and cannot be exploited to unravel the biological processes behind clonal evolution. In the last few years, functional single-cell omics has improved our understanding of cancer heterogeneity. This approach requires isolation and identification of single cells starting from an entire population. A cell suspension obtained by tumor tissue dissociation or hematological material can be manipulated using different techniques to separate individual cells, employed for single-cell downstream analysis. Single-cell data can then be used to analyze cell-cell diversity, thus mapping evolving cancer biological processes. Despite its unquestionable advantages, single-cell analysis produces massive amounts of data with several potential biases, stemming from cell manipulation and pre-amplification steps. To overcome these limitations, several bioinformatic approaches have been developed and explored. In this work, we provide an overview of this entire process while discussing the most recent advances in the field of functional omics at single-cell resolution.

Potential Therapeutic Targets for Luminal Androgen Receptor Breast Cancer: What We Know so Far.

Luminal Androgen Receptor Breast Cancers (LAR BCs) are characterized by a triple negative phenotype and by the expression of Androgen Receptor (AR), coupled with luminal-like genomic features. This unique BC subtype, accounting for about 10% of all triple negative BC, has raised considerable interest given its ill-defined clinical behavior and the chance to exploit AR as a therapeutic target. The complexity of AR activity in BC cells, as revealed by decades of mechanistic studies, holds promise to offer additional therapeutic options beyond mere AR inhibition. Indeed, preclinical and translational evidence showed that several pathways and mediators, including PI3K/mToR, HER2, BRCA1, cell cycle and immune modulation, can be tackled in LAR BCs. Moving from bench to bedside, several clinical trials tested anti-androgen therapies in LAR BCs, but their results are inconsistent and often disappointing. More recently, studies exploring combinations of anti-androgen agents with other targeted therapies have been designed and are currently ongoing. While the results from these trials are awaited, a concerted effort will be needed to find the biological vulnerabilities of LAR BCs which may disclose new and effective therapeutic targets, eventually improving patients' outcomes.

Glucose-dependent effect of insulin receptor isoforms on tamoxifen antitumor activity in estrogen receptor-positive breast cancer cells.

Introduction: Breast cancer is the most common malignancy in women, and it is linked to several risk factors including genetic alterations, obesity, estrogen signaling, insulin levels, and glucose metabolism deregulation. Insulin and Insulin-like growth factor signaling exert a mitogenic and pro-survival effect. Indeed, epidemiological and pre-clinical studies have shown its involvement in the development, progression, and therapy resistance of several cancer types including breast cancer. Insulin/Insulin-like growth factor signaling is triggered by two insulin receptor isoforms identified as IRA and IRB and by Insulin-like growth factor receptor I. Both classes of receptors show high homology and can initiate the intracellular signaling cascade alone or by hybrids formation. While the role of Insulin-like growth factor receptor I in breast cancer progression and therapy resistance is well established, the effects of insulin receptors in this context are complex and not completely elucidated. Methods: We used estrogen-dependent insulin-like growth factor receptor I deleted gene (MCF7IGFIRKO) breast cancer cell models, lentivirally transduced to over-express empty-vector (MCF7IGFIRKO/EV), IRA (MCF7IGFIRKO/IRA) or IRB (MCF7IGFIRKO/IRB), to investigate the role of insulin receptors on the antiproliferative activity of tamoxifen in presence of low and high glucose concentrations. The tamoxifen-dependent cytotoxic effects on cell proliferation were determined by MTT assay and clonogenic potential measurement. Cell cycle and apoptosis were assessed by FACS, while immunoblot was used for protein analysis. Gene expression profiling was investigated by a PCR array concerning genes involved in apoptotic process by RT-qPCR. Results: We found that glucose levels played a crucial role in tamoxifen response mediated by IRA and IRB. High glucose increased the IC50 value of tamoxifen for both insulin receptors and IRA-promoted cell cycle progression more than IRB, independently of glucose levels and insulin stimulation. IRB, in turn, showed anti-apoptotic properties, preserving cells' survival after prolonged tamoxifen exposure, and negatively modulated pro-apoptotic genes when compared to IRA. Discussion: Our findings suggest that glucose levels modify insulin receptors signaling and that this event can interfere with the tamoxifen therapeutic activity. The investigation of glucose metabolism and insulin receptor expression could have clinical implications in Estrogen Receptor positive breast cancer patients receiving endocrine treatments.

Additional Genetic Alterations and Clonal Evolution of MPNs with Double Mutations on the MPL Gene: Two Case Reports.

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are two of the main BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) characterized by abnormal megakaryocytic proliferation. Janus kinase 2 (JAK2) mutations are detected in 50-60% of ET and PMF, while myeloproliferative leukemia (MPL) virus oncogene mutations are present in 3-5% of cases. While Sanger sequencing is a valuable diagnostic tool to discriminate the most common MPN mutations, next-generation sequencing (NGS) is a more sensitive technology that also identifies concurrent genetic alterations. In this report, we describe two MPN patients with simultaneous double MPL mutations: a woman with ET presenting both MPLV501A-W515R and JAK2V617F mutations and a man with PMF displaying an uncommon double MPLV501A-W515L. Using colony-forming assays and NGS analyses, we define the origin and mutational landscape of these two unusual malignancies and uncover further gene alterations that may contribute to the pathogenesis of ET and PMF.

High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.

Purpose: Chronic Myeloid Leukemia (CML) is a clonal disorder of the hematopoietic stem cell caused by expression of the BCR::ABL1 oncoprotein. High BCR::ABL1 levels have been associated to proliferative advantage of leukemic cells, blast crisis progression and tyrosine kinase inhibitors (TKIs) inefficacy. We have previously shown that high BCR::ABL1/GUSIS transcripts measured at diagnosis are associated with inferior responses to standard dose Imatinib (IM). However, the mechanisms underlying the higher rates of disease progression and development of TKIs resistance dependent on elevated BCR::ABL1 levels remain unclear. Methods: Leukemic cells were collected from CML patients showing, at diagnosis, high or low BCR::ABL1/GUSIS. BCR::ABL1 expression levels were measured using real-time PCR. Short-term culture and long-term culture-initiating cells assays were employed to investigate the role of BCR::ABL1 gene-expression levels on proliferation, clonogenicity, signal transduction, TKIs responsiveness and self-renewal ability. Cell division was performed by carboxyfluorescein-succinimidyl ester (CFSE) assay. Results: We found that BCR::ABL1 oncogene expression levels correlate in both PMNs and CD34+ cells. Furthermore, high oncogene levels increased both proliferation and anti-apoptotic signaling via ERK and AKT phosphorylation. Moreover, high BCR::ABL1 expression reduced the clonogenicity of leukemic CD34+ cells and increased their sensitivity to high doses IM but not to those of dasatinib. Furthermore, we observed that high BCR::ABL1 levels are associated with a reduced self-renewal of primitive leukemic cells and, also, that these cells showed comparable TKIs responsiveness with cells expressing lower BCR::ABL1 levels. Interestingly, we found a direct correlation between high BCR::ABL1 levels and reduced number of quiescent leukemic cells caused by increasing their cycling. Conclusion: Higher BCR::ABL1 levels improving the proliferation, anti-apoptotic signaling and reducing self-renewal properties cause an increased expansion of leukemic clone.

Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study.

BACKGROUND: Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients. METHODS: We performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. RESULTS: PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88-6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17-45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12-20.56; p = 0.035). CONCLUSIONS: This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

IRF5 promotes the proliferation of human thyroid cancer cells.

BACKGROUND: Interferon Regulatory Factor 5 is a transcription factor that regulates the expression of genes involved in the response to viral infection and in the stimulation of the immune system. Moreover, multiple studies have demonstrated that it negatively regulates cell growth and oncogenesis, favoring cell differentiation and apoptosis.Thyroid carcinoma represents 98% of all thyroid malignancies and has shown a steady increase in incidence in both the USA and western European countries. FINDINGS: We investigated the expression, localization and function of IRF5 in thyroid cancer cells and found that it is highly expressed in both primary and immortalized thyroid carcinomas but not in normal thyrocytes. IRF5 levels were variably modulated by Interferon alpha but IRF5 only localized in the cytoplasmic compartment, thus failing to induce p21 expression as previously reported in different cell models. Furthermore, ectopic IRF5 increased both the proliferation rate and the clonogenic potential of malignant thyroid cells, protecting them from the cytotoxic effects of DNA-damaging agents. These results were directly attributable to IRF5, as demonstrated by the reduction in colony-forming ability of thyroid cancer cells after IRF5 silencing. An IRF5-dependent induction of endogenous B-Raf observed in all thyroid cancer cells might contribute to these unexpected effects. CONCLUSIONS: These findings suggest that, in thyroid malignancies, IRF5 displays tumor-promoting rather than tumor-suppressor activities.