Chromosome 9p21 Region Research Articles

The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.

A genome wide linkage scan of metacarpal size and geometry in the Framingham Study

Bone geometry is a significant component of bone strength, and has a clinical utility in predicting fractures and quantifying bone loss. Bone geometry is known to have a substantial genetic component. We performed linkage analysis to identify chromosomal regions governing metacarpal bone geometry. A genome-wide scan (with a set of 615 markers with spacing of approximately 5.7 cM) was performed on 1,702 individuals from 330 extended families of the Framingham Study. Midshaft width was measured and several indices calculated, namely Metacarpal Cortical Thickness (MCT), Cortical Index (MCI), and Section Modulus (MZ), using digitized X-rays of 1,380 participants (men, n = 666, mean age 55.2 yr, women, n = 714, 55.5 yr). Metacarpals 2, 3, and 4 were averaged. Heritability was significant for all indices, ranging from 0.51 to 0.72. Linkage analysis of indices adjusted for age, age(2), and estrogen status in women, identified chromosomal regions 6p21, 9p21, 11q21-q22, and Xq26-Xq27, with LOD scores >2.0. Additional adjustment for smoking, height, and BMI, generally reduced the LOD scores. Finally, bivariate linkage analysis confirmed that a QTL on chr. 6 (51 cM) was shared by midshaft width and MZ (LOD = 2.40, adjusted for all covariates). Neither MCT nor MCI shared linkage loci with width or MZ. In conclusion, we have identified chromosomal regions potentially linked to bone geometry. Genes in these regions may regulate bone geometry via effects on body size. Identification and subsequent characterization of loci for bone geometry can further elucidate the genetic contributions to bone's resistance to stress.

Loss of the eukaryotic initiation factor 3f in melanoma

Aberrant regulation of the translation initiation is known to contribute to tumorigenesis. eIF3 plays an important role in translation initiation. eIF3f is the p47 subunit of the eIF3 complex whose function in cancer is not clear. Initial studies from our group indicated that eIF3f expression is decreased in melanoma. Overexpression of eIF3f inhibits translation and induces apoptosis in melanoma cells. The eIF3f gene is located at chromosome region 11p15.4. Loss of 11p15.4 is a common event in many tumors including melanoma. In order to investigate the molecular mechanism of the decreased expression of eIF3f in melanoma, we performed loss of heterozygosity (LOH) analysis in 24 melanoma specimens using three microsatellite markers encompassing the eIF3f gene. We showed that the prevalence of LOH ranged from 75% to 92% in melanoma. We also performed eIF3f gene copy number analysis using quantitative real-time PCR to further confirm the specific allelic loss of the eIF3f gene in melanoma. We demonstrated a statistically significant decrease of the eIF3f gene copy number in melanoma compared with normal tissues with a tumor/normal ratio of 0.52. To further elucidate the somatic genetic alterations, we carried out mutation analysis covering the entire coding region and 5'UTR of the eIF3f gene in melanoma tissues and cell lines. Despite some polymorphisms, we did not find any mutations. Furthermore, immunohistochemistry analysis demonstrated that eIF3f protein expression is decreased in melanoma compared to benign nevi. These data provide new insight into the understanding of the molecular pathogenesis of eIF3f during melanoma tumorigenesis.

Genome-wide association studies of coronary artery disease: have the results of replication studies been replicable?

The recent wave of publications describing genome-wide association (GWA) studies of coronary artery disease (CAD) is beginning to wane. These GWA studies have identified a host of genetic variants that are associated with CAD. As expected, within a span of a few months this initial flood of GWA studies has inspired a matching surge of replication studies. At this juncture it is perhaps pertinent to ask the question: Have the results generated from these studies, thus far, been reproducible? Findings from the first GWA study for CAD were reported by the Wellcome Trust Case Control Consortium.1 A day later, two independent studies2,3 simultaneously reported that two variants in the chromosome 9p21 region are significantly associated with two closely related disease phenotypes, CAD and myocardial infarction (MI), respectively. An association with chromosome 9p21 had not been reported in previous studies of CAD or myocardial infarction. This region contains the sequences of genes coding for two cyclin-dependent kinase inhibitors, CDKN2A (encoding p16INK4a) and CDKN2B (p15INK4b). In less than 2 months, a replication study carried out using the GWA approach confirmed the original findings … *Corresponding author. Tel: +65 67725708, Fax: +65 67742796, Email: paehck{at}nus.edu.sg

Can Fishing for New Genes Catch Patients at Risk of Coronary Artery Disease?

With rapid and dramatic success, the Genome-Wide Association Study (GWAS) has proven to be an effective tool for the discovery of unsuspected genetic determinants of common disorders and has opened a new armamentarium for the pathophysiologic exploration of numerous diseases. The best illustration of the feasibility and strength of the GWAS approach was demonstrated in June of 2007 by a consortium of more than 50 British research groups participating in the Wellcome Trust Case-Control Consortium (WTCCC). Working collaboratively, the WTCCC investigators studied 14 000 cases of 7 common diseases and 3000 shared controls and identified 24 independent association signals, 1 in bipolar disease, 1 in coronary disease, 9 in Crohn disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes, and 3 in type 2 diabetes, each with a statistical effect approaching or exceeding genome–wide levels of significance (1). Remarkably, the key finding in this study for coronary heart disease—a clear association between vascular risk and common variation in the region of chromosome 9p21.3—was rapidly validated in a series of similar GWAS studies, including the Cardiogenics Consortium; the Ottawa, Dallas, and Framingham Heart Studies; and the DeCode Genetics program in Iceland (2)(3)(4)(5). The chromosome 9p21.3 region contains the coding sequences of genes for 2 cyclin-dependent kinase inhibitors known to play roles in tumor suppression, cell proliferation, and apoptosis. Thus, these validated GWAS findings for coronary disease not only raise the concept of a novel genetic determinant of disease, but also provide strong pathophysiologic support for prior work linking each of these processes directly to atherogenesis and plaque disruption. What is …

Genomewide Linkage in a Large Dutch Family With Intracranial Aneurysms

Approximately 2% of the general population harbor intracranial aneurysms. The prognosis after rupture of an intracranial aneurysm is poor; 50% of the patients die as a result of the rupture. Familial occurrence of intracranial aneurysms suggests there are genetic factors involved in the development of such aneurysms. A large, consanguineous pedigree with 7 of 20 siblings affected by intracranial aneurysms was compiled and a genomewide linkage analysis on this family was performed using Illumina's single nucleotide polymorphism-based linkage panel IV, which includes 5861 single nucleotide polymorphisms. A nonparametric linkage affecteds-only approach with GENEHUNTER was used. Two loci with suggestive linkage (nonparametric linkage=3.18) on chromosome regions 1p36 and Xp22 were identified. Additional microsatellite markers were genotyped in the 2 candidate loci and showed suggestive linkage to the locus on chromosome 1 with a nonparametric linkage of 3.18 at 1p36.11-p36.13 and significant linkage to the locus on chromosome X with a nonparametric linkage of 4.54 at Xp22.2-p22.32. The 2 potential loci for intracranial aneurysms, which we identified in this large Dutch family, overlap with loci that have already been identified in previous linkage studies from different populations. Identification of genes from these loci will be important for a better understanding of the disease pathogenesis.

Molecular genetics of myocardial infarction

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for MI include hypertension, hypercholesterolemia or dyslipidemia, diabetes mellitus, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Disease prevention is an important strategy for reducing the overall burden of MI, with the identification of markers for disease risk being key both for risk prediction and for potential intervention to lower the chance of future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to coronary heart disease (CHD) or MI, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. In this review, we summarize both candidate loci for CHD or MI identified by linkage analyses and candidate genes examined by association studies. We also review in more detail studies that have revealed the association with MI or CHD of polymorphisms in MTHFR, LPL, and APOE by the candidate gene approach and those in LTA and at chromosomal region 9p21.3 by genome-wide scans. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of CHD and MI.

DNA Gains and Losses of Chromosome in Laryngeal Squamous Cell Carcinoma Using Comparative Genomic Hybridization

PurposeA larynx squamous cell carcinoma (LSCC) is one of the most common forms of cancer and may exhibit various complex karyotypes.Materials and MethodsWe used comparative genomic hybridization (CGH) to analyze DNA gains and losses in 15 squamous cell carcinomas that consisted of 4 glottic, 10 supraglottic, and 1 transglottic localization samples.ResultsThe majority of the chromosomal alterations detected were gains: 3 samples of LSCCs revealed high level amplification, while 6 samples displayed gains in various chromosomal regions (17p, 3p, 4p, 5p, 6q, 8p, 9p, 14q, 18p and Xq). One sample was found to have losses (chromosomes 15q and 22q) and 5 had normal CGH profiles.ConclusionMany of these gained regions (4p, 5p, 8p, 10q, 18q and Xq) were novel sites, which may harbor oncogene(s) that potentially play an important role in squamous cell tumorigenesis and progression at supraglottic localizations.

3p Microsatellite Signature in Exhaled Breath Condensate and Tumor Tissue of Patients with Lung Cancer

Our group has recently demonstrated the possibility of studying microsatellite alterations (MAs) of 3p in the DNA of exhaled breath condensate (EBC) of patients with non-small cell lung cancer (NSCLC). To verify whether MAs analyzed in DNA from EBC reflect a profile of alterations present in tumor tissue of NSCLC. Fifty-nine subjects undergoing histologic diagnosis for clinical suspicion of lung cancer entered the study: 41 were found to have NSCLC and 18 to have nonneoplastic diseases. All subjects underwent allelotyping on DNA from whole blood, EBC, and lung tissue removed for histologic diagnosis by analyzing a panel of five microsatellites located in chromosomal region 3p. Results obtained from DNA of the three biological sites and nonneoplastic tissues from controls were compared. MAs in DNA from tumor tissues and EBC of each patient with cancer presented an overlapping profile of loss of heterozygosity and microsatellite instability. An MA profile of DNA of lung tissue reflecting the DNA of EBC profile from controls was also confirmed. Smoking status was associated with the presence of MAs in patients with NSCLC and in control subjects. We demonstrated that MAs in DNA from EBC of patients with NSCLC are significantly more frequent than in control subjects. More interesting, the MA profile of DNA from EBC corresponds to that from lung cancer tissue of each patient with NSCLC.

NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia

The recurrent translocation t(8;16)(p11;p13) is found in about 6.5% of acute myeloid leukemias (AMLs) of the M4/M5-FAB subtypes. These poor prognosis AMLs are associated with erythrophagocytosis by blast cells. The translocation results in the fusion of the MYST3 gene (also known as MOZ) on chromosome region 8p11 to the CREBBP gene (also known as CBP) on chromosome region 16p13.1, 2, 3 In the same type of AML, the t(10;16)(q22;p13) fuses MYST3-homolog MYST4 to CREBBP4 and the t(8;22)(p11;q13) fuses MYST3 to CREBBP-homolog EP300.5 MYST3, MYST4, CREBBP and EP300 encode transcriptional regulators and acetyltransferases. MYST3 is also fused to NCOA2 in the inv(8)(p11q13).6, 7 NCOA1/SRC1, NCOA2/TIF2 and NCOA3 are paralogous genes encoding transcription coactivators of the p160 family.8 Some rearrangements involving NCOA genes and MYST3 or MYST4 genes have not been reported yet, but have been suspected or predicted on the basis of homology relations.4 We report here a new type of translocation, t(8;20)(p11;q13), which occurs in an M5-AML and fuses MYST3 to NCOA3.

519 POSTER Differences in epigenetic silencing of 9p21 locus tumour suppressor genes CDKN2A/p14(ARF)/CDKN2B in HPV16 positive and negative HNSCCs

Homozygous deletions of human chromosomal region 9p21 occur frequently in malignant melanoma and are associated with the loss of the tumor suppressor genes p16(INK4a) and p15(INK4b). In the same chromosomal region the methylthioadenosine phosphorylase (MTAP) gene is localized and therefore may also serve as a tumor suppressor gene. The aim of this study was to analyze MTAP mutations and expression patterns in malignant melanomas. To examine the MTAP gene and expression of MTAP protein we screened 9 human melanoma cell lines and primary human melanocytes by reverse transcriptase-polymerase chain reaction, sequencing, and immunoblotting. Analyzing the melanoma cell lines we found significant down-regulation of MTAP mRNA expression. In only one cell line, HTZ19d, this was due to homozygous deletion of exon 2 to 8 whereas in the other cell lines promoter hypermethylation was detected. MTAP expression was further analyzed in vivo by immunohistochemical staining of 38 tissue samples of benign melanocytic nevi, melanomas, and melanoma metastases. In summary, we demonstrate significant inverse correlation between MTAP protein expression and progression of melanocytic tumors as the amount of MTAP protein staining decreases from benign melanocytic nevi to metastatic melanomas. Our results suggest an important role of MTAP inactivation in the development of melanomas. This finding may be of great clinical significance because recently an association between MTAP activity and interferon sensitivity has been suggested.

Loss of mXinα, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXinalpha and mXinbeta. The human homolog of mXinalpha, Cmya1, maps to chromosomal region 3p21.2-21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXinalpha-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXinbeta likely provides partial compensation and accounts for the viability of the mXinalpha-null mice. Ultrastructural studies of mXinalpha-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXinalpha-null mice, there is a significant decrease in the expression level of p120-catenin, beta-catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXinalpha-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXinalpha-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXinalpha-deficient hearts. Thus mXinalpha functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXinalpha-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.

Index of Suspicion in the Nursery

Five days after birth at a private hospital, an infant is brought to another hospital because he is inactive and limp. The delivery was by outlet forceps after a supervised, normal pregnancy to consanguineous (uncle-niece) parents. His birthweight was 3.25 kg. According to his parents, he did not cry until 1 hour after birth, was limp, fed poorly, and a few hours later, had cyanosis of lips and nails and generalized tonic and clonic convulsions that were unresponsive to anticonvulsants and intravenous glucose. The parents were told that he had hypoxic brain injury and possibly an intracranial hemorrhage. The convulsions became less frequent once expressed human milk was provided through a nasogastric tube. The exact details of management at the private hospital are not available. The infant is the first child of the woman, who is well nourished and does not have diabetes. His weight on admission at 5 days of age is 3.66 kg, length is 49 cm, and head circumference is 33 cm. He is inactive and limp. His temperature is 97.8°F (36.6°C) and heart rate is 170 beats/min. His cry is feeble and response to pain is minimal. His anterior fontanelle is normal, hydration is adequate, Moro reflex is incomplete, and sucking and rooting reflexes are poor. He does not have syndromic features or acidosis. No additional findings are revealed in the remainder of the general and systemic evaluations. The results of a complete blood count; measurement of electrolytes, calcium, and bilirubin; review of the cerebrospinal fluid and urinalysis; electrocardiography and radiography of the chest and skull; and abdominal ultrasonography are normal. Cultures of blood, cerebrospinal fluid, and urine are sterile. Oxygen saturation is 98%. Blood glucose on admission is 41 mg/dL (2.28 mmol/L) and is monitored every 1 to 4 hours. Urine ketones are negative. The …

Common chromosomal abnormalities in mycosis fungoides transformation

To identify cytogenetic features of large cell transformation in mycosis fungoides (T-MF), we selected in 11 patients, 16 samples either from skin tumors (13), lymph node (1), or peripheral blood cells (2) collected at the time of the transformation. Comparative genomic hybridization (CGH), G-banding, fluorescence in situ hybridisation (FISH), multicolour FISH (mFISH), and DNA content analysis were used. Fifteen samples displayed unbalanced CGH profiles, with gains more frequently observed than losses. Recurrent chromosomal alterations were observed for chromosomes 1, 2, 7, 9, 17, and 19. The most common imbalances were gain of chromosome regions 1p36, 7, 9q34, 17q24-qter, 19, and loss of 2q36-qter, 9p21, and 17p. In six samples 1p36-pter gain was associated with 9q34-qter gain and whole chromosome 19 gain. In five of these samples whole or partial gain of chromosome 17 was also observed. No specific pattern was seen with regard to the expression of the CD30 antigen by tumor cells. Cytogenetics and/or DNA content analysis of skin tumor cells revealed an abnormal chromosome number in all tested cases (n = 7) with DNA ploidy ranging from hyperdiploid (2.78) to hypotetraploid (3.69) (mean 3.14+/-0.38). Thus, T-MF displayed frequent chromosomal imbalances associated with hypotetraploidy.

TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphism TNF*‐857 independent of the PSORS1 risk allele

Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions -238 and -308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. SNPs in the promoter of the TNF (-238G/A, -308G/A, -857C/T, and -1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334-2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele.

The function of the putative tumor suppressor Nit1 in lymphocytes (84.7)

Abstract The mammalian Nit1 gene is homologous to bacterial and plant nitrilases. In the fruit fly D. melanogaster and warms C. elegans, Nit1 is fused to the Fhit gene, whereas in mammals, FHIT and NIT1 are separate genes. FHIT is a tumor suppressor gene located at chromosome region 3p14.2, encompassing the common fragile site of the human genome. Somatic loss of Fhit in humans is associated with cancers in a wide variety of sites, including lung, kidney, stomach, pancreas, cervix, ovary, head and neck, breast, and hematopoetic cells. Proteins that engage in fusion events are expected to jointly participate in a biochemical or cellular pathway and/or to physically interact. Therefore, Nit1 may be functionally related to Fhit. Overexpression of Fhit and Nit1 can induce apoptosis. There was evidence showing that Fhit can induce FADD-mediated cell death. In this study, the in vivo function of Nit1 was analyzed using the Nit1 knockout mice. Various in vitro and in vivo analyses showed that Nit1 plays an important role in regulating cell cycle and proliferation in T lymphocytes.

Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism

Neonatal hyperinsulinism is the most important cause of hypoglycemia in infancy (1,2). The inappropriate oversecretion of insulin is responsible for profound hypoglycemia, requiring aggressive treatment to prevent brain damage (1–3). Neonatal hyperinsulinism is often resistant to medical therapy (1–4), and pancreatectomy is required for many sufferers (1,5–6). The histopathological lesions associated with neonatal hyperinsulinism may be described as diffuse or focal (7–8). Focal adenomatous islet cell hyperplasia is sporadic and has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of the sulfonylurea receptor 1 ABCC8 gene (9,10) or the inward-rectifying potassium channel Kir6.2 (KCNJ11) (10) in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells (9–11). Diffuse hyperinsulinism may be familial and arises from the autosomal recessive inheritance of mutations in both ABCC8 (12) and KCNJ11 (13–14) genes. The therapeutic outcome for the patients is heavily dependent on distinguishing between the two histopathological lesions. Diffuse hyperinsulinisms, which are unresponsive to medical treatment, require extensive pancreatectomy, with a high risk of diabetes (5,15–16). Conversely, focal hyperinsulinism can be cured by limited pancreatectomy (6,17). Genetic counseling is dramatically different, as focal hyperinsulinism is considered a sporadic molecular event with a very low recurrence risk (10,18), while diffuse …

Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease

Epithelial cancers inflict a heavy human and social burden. It was estimated [Tyczynski JE, Bray F, Parkin DM. Lung cancer in Europe in 2000: epidemiology, prevention, and early detection. Lancet Oncol 2003;4:45-55 (Review)] that in Europe, in the year 2000, 347 000 persons died of lung cancer alone, the deadliest cancer disease. Loss of heterozygosity and large homozygous deletions of the human chromosome region 3p21 are especially frequent in epithelial cancers of several organs. In fact, 3p21 is a very peculiar region of the genome harbouring, tightly clustered, several types of cancer-causing genes (CCG) (Lerman MI, Minna JD. The 630 kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumour suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res 2000;60:6116-33). Current results show that, unlike it was thought initially, many tumour suppressor genes (TSG) are located close by even in small genomic regions. They may be involved, perhaps with varying role, in different types of tumour, and may be influenced by the genetic background of different human populations as well as by environmental pollutants (cigarette smoking, professional exposure). This review will discuss methods of molecular analysis of genomic deletions to uncover CCG at 3p21, will summarize the present knowledge regarding the TSGs located in this region, and will describe a possible model of epithelial cancer pathogenesis.

New types of MYST3-CBP and CBP-MYST3 fusion transcripts in t(8;16)(p11;p13) acute myeloid leukemias

The t(8;16)(p11;p13) translocation, associated with poor prognosis acute monocytic leukemia, fuses MYST3 on chromosome region 8p11 to CBP on chromosome region 16p13. Two types of MYST3-CBP and CBP-MYST3 fusion transcripts have been identified in patients. We describe two new types of MYST3-CBP transcripts and a new primer set.

Identification of two Novel Frameshift Mutations in the KCNJ11 gene in two Italian patients affected by Congenital Hyperinsulinism of Infancy

Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATP-sensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11, but to date only twenty mutations have been identified in KCNJ11, most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.