In early 1995, I established the oncogenetics service at the Genetics Institute of the Sheba Medical Center in Israel. The purpose of this article is to describe the key points and issues that were ...raised throughout my personal journey since then: physician and public awareness; ethical and legal issues; guidelines for oncogenetic counseling; the development of oncogenetic testing within the unique Israeli reality of the limited spectrum of
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mutations; high-risk vs. population screening; and the definition and implementation of guidelines for surveillance of asymptomatic mutation carriers. Since 1995, oncogenetics has been transformed from a rare oddity to a pivotal player, and it represents a successful example of implementing personalized preventive medicine by identifying and providing care and by offering means for early detection and risk reduction for adults who are genetically predisposed to develop a potentially life-threatening disease-cancer in this case. Lastly, I outline my personal vision for the possible way forward for oncogenetics.
The serotonin 4 receptor, 5-HT₄R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such ...as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer's disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT₄R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT₄R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT₄R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT₄R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.
Metastasis is the primary cause for mortality in breast cancer. MicroRNAs, gene expression master regulators, constitute an attractive candidate to control metastasis. Here we show that breast cancer ...metastasis can be prevented by miR-96 or miR-182 treatment, and decipher the mechanism of action. We found that miR-96/miR-182 downregulate Palladin protein levels, thereby reducing breast cancer cell migration and invasion. A common SNP, rs1071738, at the miR-96/miR-182-binding site within the Palladin 3'-UTR abolishes miRNA:mRNA binding, thus diminishing Palladin regulation by these miRNAs. Regulation is successfully restored by applying complimentary miRNAs. A hydrogel-embedded, gold-nanoparticle-based delivery vehicle provides efficient local, selective, and sustained release of miR-96/miR-182, markedly suppressing metastasis in a breast cancer mouse model. Combined delivery of the miRNAs with a chemotherapy drug, cisplatin, enables significant primary tumour shrinkage and metastasis prevention. Our data corroborate the role of miRNAs in metastasis, and suggest miR-96/miR-182 delivery as a potential anti-metastatic drug.
Kaposi's sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, ...secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear.
Here we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKKβ) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTOR-dependent increase in HIF-1α and HIF-2α protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation in vivo. Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression.
Our findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS.
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell ...survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders.
In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2 . For ...carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts ( P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.
Significance Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to very high risks of breast and ovarian cancer. For carriers of these mutations, risk-reducing surgery significantly reduces morbidity and mortality. General population screening for BRCA1 and BRCA2 mutations in young adult women could be feasible if accurate estimates of cancer risk for mutation carriers could be obtained. We determined that risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained from the general population are as high as for mutation carriers ascertained through personal or family history of cancer. General screening of BRCA1 and BRCA2 would identify many carriers who are currently not evaluated and could serve as a model for population screening for genetic predisposition to cancer.
Following vaccination of Israeli population with Pfizer-BioNTech COVID-19 Vaccine, an unusual increase in axillary-lymphadenopathy was noted. This study assesses the rate and magnitude of this trend ...from breast-imaging standpoint.
Participants undergoing breast-imaging, in whom isolated axillary-lymphadenopathy was detected were questioned regarding SARS-CoV-2 vaccine to the ipsilateral arm. Patients' and imaging characteristics were statistically compared. In order to perform a very short-term follow-up, twelve healthy vaccinated medical staff-members, underwent axillary-ultrasound shortly after the second dose, and follow-up.
Axillary-lymphadenopathy attributed to vaccination was found in 163 women undergoing breast-imaging, including BRCA-carriers. During the study, number of detected lymphadenopathies increased by 394% (p = 0.00001) in comparison with previous 2 consecutive years. Mean cortical-thickness of abnormal lymph-nodes after second dose vaccination was 5 ± 2 mm. Longer lymph-node diameter after second vaccination was noted (from 15 ± 5 mm, to 18 ± 6 mm, p = 0.005). In the subgroup of medical staff members, following trends were observed: in patients with positive antibodies, lymph-node cortical-thickness was larger than patients with negative serology (p = 0.03); lymph-node cortical-thickness decreased in 4-5 weeks follow-up (p = 0.007). Lymphadenopathy was evident on mammography in only 49% of cases.
Vaccine-associated lymphadenopathy is an important phenomenon with great impact on breast-imaging clinic workload. Results suggest the appearance of cortical thickening shortly after both doses. Positive serology is associated with increased lymph-node cortical-thickness. In asymptomatic vaccinated women with ipsilateral axillary-lymphadenopathy as the only abnormal finding, radiological follow-up is probably not indicated. BRCA-carriers, although at higher risk for breast-cancer, should probably receive the same management as average-risk patients.
Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse ...cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.
To evaluate the long-term survival of ovarian cancer (OvC) patients in total and by BRCA1/2 mutation status.
In a nationwide case-control study on OvC conducted in Israel between 1994 and 1999, 779 ...Jewish women with epithelial invasive OvC were tested for the three Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) genes and followed for survival up to 2003. Of the 605 women of Ashkenazi origin, 213 (35.2%) carried a mutation in the BRCA1/2 genes. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method, log-rank tests, and stepwise Cox regression model were used for survival analyses.
The 5-year survival rate for the entire group was 39%. Median survival for carriers was significantly longer than for noncarriers (53.7 v 37.9 months, respectively; P = .002). This differential survival was pronounced among women diagnosed at stages III to IV (5-year survival rates of 38.1% and 24.5% for carriers and noncarriers, respectively; P < .001) and for women with poor grade (45.4% v 31.5%, for carriers and noncarriers, respectively; P < .001). These results remained significant after controlling for age at diagnosis, grade, and morphology. This benefit in prognosis was seen for both BRCA1 and BRCA2 carriers compared with noncarriers. During the study period (median follow-up, 6.2 years), being a BRCA1/2 mutation carrier decreased the mortality rate by 28%.
This study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be due to distinct clinical behavior and/or to a better response to chemotherapy.
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