Chr20q Amplification Defines a Distinct Molecular Subtype of Microsatellite Stable Colorectal Cancer.

Colorectal cancer is the third leading cause of cancer-related death in the United States. About 15% of colorectal cancers are associated with microsatellite instability (MSI) due to loss of function in the DNA mismatch repair pathway. This subgroup of patients has better survival rates and is more sensitive to immunotherapy. However, it remains unclear whether microsatellite stable (MSS) patients with colorectal cancer can be further stratified into subgroups with differential clinical characteristics. In this study, we analyzed The Cancer Genome Atlas data and found that Chr20q amplification is the most frequent copy number alteration that occurs specifically in colon (46%) and rectum (61%) cancer and is mutually exclusive with MSI. Importantly, MSS patients with Chr20q amplification (MSS-A) were associated with better recurrence-free survival compared with MSS patients without Chr20q amplification (MSS-N; P = 0.03). MSS-A tumors were associated with high level of chromosome instability and low immune infiltrations. In addition, MSS-A and MSS-N tumors were associated with somatic mutations in different driver genes, with high frequencies of mutated TP53 in MSS-A and mutated KRAS and BRAF in MSS-N. Our results suggest that MSS-A and MSS-N represent two subtypes of MSS colorectal cancer, and such stratification may be used to improve therapeutic treatment in an individualized manner. SIGNIFICANCE: This study shows that chromosome 20q amplification occurs predominately in microsatellite-stable colorectal cancer and defines a distinct subtype with good prognosis, high chromosomal instability, distinct mutation profiles, and low immune infiltrations.

High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review.

BACKGROUND: A subset of undifferentiated small round cell sarcomas (USRCSs) is currently being recognized as emerging entities with unique gene fusions: CIC-DUX4 (the area of focus in this article), BCOR-CCNB3, or CIC-FOXO4 gene fusions. CIC-DUX4 and CIC-FOXO4 fusions have been reported in soft tissue tumors, while BCOR-CCNB3 fusion with an X chromosomal inversion was described in both bone and soft tissue tumors. CIC-DUX4 fusion can either harbor t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13), while t(4;19)(q35;q13.1) is reported more commonly. CASE REPORT: The aim of this study is to share a new case report of a 36-year-old woman who had a rapidly growing mass in her right upper thigh, which was found to be an undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion was confirmed by cytogenetic testing. Combined modality treatment with surgery, radiation, and chemotherapy was used and achieved a good response. A review of the literature of the reported cases with CIC-DUX4 fusions including both t(4;19) and t(10;19) translocations revealed a total of 44 cases reported. Out of these 44 cases, 33 showed t(4;19)(q35;q13.1) translocation compared to 11 cases with t(10;19)(q26.3;q13). CONCLUSIONS: Undifferentiated small round cell sarcomas are aggressive tumors. Their treatment includes surgery, chemotherapy, and radiation. Resistance to chemotherapy is common. Lung and brain are common sites of metastasis, with associated poor prognosis. Generally, median survival is less than 2 years. Newer techniques have been developed recently which helped identify a subset of previously unclassifiable sarcomas, with promising prognostic value.

[Correlation of chromosome 1p and 19q status and expression of R132H mutant IDH1 protein in oligodendroglial tumors].

OBJECTIVE: To correlate the presence of chromosome 1p/19q deletion with the expression of R132H mutant IDH1 status in oligodendroglial tumors, and to explore molecular markers for predicting chemosensitivity of oligodendroglial tumors. METHODS: The study included 75 oligodendroglial tumors (38 oligodendrogliomas and 37 oligoastrocytomas). Immunohistochemistry was used to detect the expression of R132H mutant IDH1 protein, and fluorescence in situ hybridization (FISH) was employed to detect 1p/19q deletion. RESULTS: Deletion of chromosome 1p and/or 19q was detected in 37 cases (37/75, 49.3%), among which co-deletion of 1p and 19q was seen in 34 cases (closely correlated, P < 0.01). Oligodendrogliomas WHOIIhad a slightly higher deletion rate than oligodendrogliomas WHO III, although without statistical significance. Oligodendrogliomas WHO IIand WHO III had a significantly higher deletion rate of chromosome 1p/19q than oligoastrocytomas WHO II and WHO III (P < 0.05). While combined loss of 1p/19q was always detected in oligodendrogliomas when FISH was positive, isolated 1p or 19q deletion was only found in oligoastrocytomas. The expression of R132H mutant IDH1 was detected in 51 of 75 cases (68.0%), in which oligodendrogliomas had a higher positive rate than oligoastrocytomas. Statistical analysis demonstrated a significant correlation between the expression of R132H mutant IDH1 protein and the presence of combined 1p/19q deletion in oligodendrogliomas (P < 0.05). CONCLUSIONS: A significant correlation was observed between the expression of R132H mutant protein and 1p/19q LOH.Expression of 132H mutant IDH1 protein is the potential biomarker for predicating the presence of 1p/19q deletion in oligodendrogliomas.

Epilepsy due to 20q13.33 subtelomere deletion masquerading as pyridoxine-dependent epilepsy.

A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy. Array comparative genomic hybridization (CGH) demonstrated a 1.5-Mb terminal deletion of the long arm of chromosome 20, which included deletion of the KCNQ2 and CHRNA4 genes, both of which have been associated with specific epilepsy syndromes. We suggest that this boy's neonatal epilepsy and neurodevelopmental disabilities are secondary to this deletion and that his clinical response to pyridoxine was coincidental. This patient's history emphasizes the utility of array CGH in the evaluation of children with epilepsy of unknown etiology.

Ictal involvement of the nigrostriatal system in subtle seizures of ring chromosome 20 epilepsy.

Studies in animal models and patients with epilepsy have suggested that basal ganglia circuits may control epileptic seizures and that striatal dopaminergic transmission may play a role in seizure modulation and interruption. Chromosome 20 [r(20)] syndrome is a well-defined chromosomal disorder characterized by epilepsy, mild-to-moderate mental retardation, and lack of recognizable dysmorphic features. Epilepsy is often the most important clinical manifestation of the syndrome, with prolonged episodes of nonconvulsive status epilepticus suggesting dysfunction in the seizure control system. We present the ictal blood oxygen level-dependent (BOLD) changes in brief seizures recorded by means of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration in a patient with [r(20)] syndrome. We observed ictal BOLD increments in a cortical-subcortical network involving substantia nigrastriatum and frontal cortex. At present, this is the first functional neuroimaging evidence of the involvement of the nigrostriatal system during ictal EEG discharges in [r(20)] syndrome supporting a role of the basal ganglia circuits in human epileptic seizures.

Genome-wide linkage of obstructive sleep apnoea and high-density lipoprotein cholesterol in a Filipino family: bivariate linkage analysis of obstructive sleep apnoea.

Increasing evidence supports an association between obstructive sleep apnoea (OSA) and metabolic syndrome (MeS) in both children and adults, suggesting a genetic component. However, the genetic relationship between the diseases remains unclear. We performed a bivariate linkage scan on a single Filipino family with a high prevalence of OSA and MeS to explore the genetic pathways underlying these diseases. A large rural family (n = 50, 50% adults) underwent a 10-cM genome-wide scan. Fasting blood was used to measure insulin, triglycerides, total cholesterol and high density lipoprotein (HDL) cholesterol. Attended overnight polysomnography was used to quantify the respiratory disturbance index (RDI), a measure of sleep apnoea. Body mass index z-scores and insulin resistance scores were calculated. Bivariate multipoint linkage analyses were performed on RDI and MeS components. OSA prevalence was 46% (n = 23; nine adults, 14 children) in our participants. MeS phenotype was present in 40% of adults (n = 10) and 48% of children (n = 12). Linkage peaks with a logarithm of odds (LOD) score >3 were demonstrated on chromosome 19q13.4 (LOD = 3.04) for the trait pair RDI and HDL cholesterol. Candidate genes identified in this region include the killer cell immunoglobulin-like receptor genes. These genes are associated with modulating inflammatory responses in reaction to cellular stress and initiation of atherosclerotic plaque formation. We have identified a novel locus for genetic links between RDI and lipid factors associated with MeS in a chromosomal region containing genes associated with inflammatory responses.

-509C>T polymorphism in the TGF-ß1 gene promoter is not associated with susceptibility to and progression of colorectal cancer in Chinese.

AIM: Colorectal cancer is common, accounting for nearly 10% of all cancers. Transforming growth factor-ß1 (TGF-ß1) is a pleiotropic cytokine that has been implicated in the pathogenesis of colorectal neoplasia. The most studied -509C>T polymorphism of TGF-ß1 gene has been associated with various kinds of cancer. This study investigated the association between this genetic variant and the risk and/or progression of colorectal cancer. METHOD: A case-control study was carried out of 150 colorectal cancer cases and 503 healthy controls. DNA was extracted from blood cell nuclear materials, and -509C>T polymorphism in the TGF-ß1 gene promoter was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Colorectal cancer tissues (n = 70) were obtained from the studied cases for measurement of TGF-ß1 mRNA expression levels. We also assessed the plasma TGF-ß1 levels of cases (n = 88) and healthy subjects (n = 120). RESULTS: The TGF-ß1 producer genotype, -509TT, was not associated with an increased risk of colorectal cancer compared with other genotypes. Colorectal cancer patients especially those with a more aggressive disease behaviour were more frequently associated with C allele. CONCLUSION: The results suggest that TGF-ß1 -509C>T polymorphism is not associated with either an increased risk or progression of colorectal cancer.

The role of genes and environment in the etiology of PCOS.

Both genes and the environment contribute to PCOS. Obesity, exacerbated by poor dietary choices and physical inactivity, worsens PCOS in susceptible individuals. The role of other environmental modifiers such as infectious agents or toxins are speculative. Phenotype confusion has characterized genetic studies of PCOS. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, the follistatin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene (but not involving this gene), as it has been identified in two separate studies, and perhaps most importantly has not yet been refuted by larger studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. To date, no gene has been identified that causes or contributes substantially to the development of a PCOS phenotype.

The role of chromosomal translocation (15;19) in the carcinoma of the upper aerodigestive tract in children.

OBJECTIVE: To further evaluate the role of chromosomal translocation (15;19) in the presentation of the carcinoma (CA) of the upper aerodigestive tract. STUDY DESIGN AND SETTING: A retrospective study at a tertiary care pediatric medical center. RESULTS: Seven patients with a mean age of 12 years presented with CA of nasopharynx (N = 2), sinonasal region (N = I), parotid gland (N = 2), or larynx (N = 2). Treatments included combinations of surgery (N = 5), chemotherapy (N = 5), and radiation therapy (N = 4). One patient with sinonasal CA and one patient with laryngeal CA had chromosomal translocation (15;19); these patients both died of their disease with a mean survival of 6 months. The 5 patients without translocation (15;19) responded well to treatment and are disease-free with a mean follow-up of 47 months. CONCLUSION: The preliminary results appear to indicate poor prognosis associated with the presentation of chromosomal translocation (15;19) despite aggressive multi-modality treatment. Further investigation is needed to better understand the cause and relationship of the translocation (15;19) and aggressive behavior of these tumors.

Mutation of the Notch 3 gene in a Thai cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy family.

The authors report the first Thai family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in which the family members had a classical history of progressive vascular dementia. The proband was a 31-year old Thai male who presented with an acute stroke in the subcortical region. His past history revealed mental disturbance, including poor judgement and regressive behavior as well as mood changes for 1 year. He did not have a history of migraine or any other vascular risk factors except for a strong family history of ischemic stroke and progressive dementia. Magnetic resonance imaging demonstrated multiple small infarctions in the subcortical white matter of the bilateral frontal, parietal and occipital lobes with another small lesion in the pons. Genetic study demonstrated a Notch 3 mutation consisting of the substitution of a nucleotide at position 406 in exon 3 leading to the replacement of an Arginine by Cysteine at position 110 in the 2nd EGF motif, which is compatable with CADASIL.

[Clinical, radiological, histopathological and genetic findings in a Danish "CADASIL" family]. / Kliniske, radiologiske, histopatologiske samt genetiske fund i en dansk "CADASIL"-familie.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare adult-onset inherited arterial disease with a distinctive neuropathological phenotype. Owing to its recent identification and variable mode of presentation, the disease is often misdiagnosed. The CADASIL gene is Notch 3 and has been mapped on chromosome 19q12 in several unrelated families. Knowledge of the phenotypic range of CADASIL, however, remains incomplete. Clinical, pathological radiological, and genetic findings in the first known Danish CADASIL pedigree are presented. Genetic testing confirmed a Notch 3 mutation. The mutation consisted of the substitution of a nucleotide at position 475 leading to the replacement of amino acid arginine for cysteine at position 133 in the third EGF motif.

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature.

About 20% of all human conceptuses are estimated to be trisomic and trisomy of all chromosomes remains a common cause of early fetal loss. Uniparental disomy (UPD) has been reported for most human chromosomes and may be an underrecognized contributor to embryonic lethality. To investigate the contribution of UPD to spontaneous abortions, we devised a genome-based screening strategy to identify holochromosomic UPD in 18 fetal losses. No cases of UPD were identified using this approach. Based on our data, UPD does not appear to be a significant contributor to early embryonic lethality. The results of the study are presented along with a review of the cases of UPD reported in the literature by chromosome, parental origin, mode of ascertainment, and phenotypic consequences due to imprinting.

[Hereditary autosomal dominant brain infarction]. / Autosomal dominant arvelig hjerneinfarktsykdom.

Some aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are reviewed. The condition causes stroke and vascular dementia. Pathological examination reveals multiple small, deep infarcts, leukoencephalopathy, and non-atherosclerotic, non-amyloid angiopathy which mainly involve the small cerebral arteries where there are severe alterations in vascular smooth-muscle cells. In hereditary autosomal dominant stroke condition patients with mutations in the human Notch 3 gene on chromosome 19 have been identified. Skin and muscle biopsy may be useful for diagnosing this condition. No causal treatment is available. Hereditary autosomal dominant stroke condition has not been diagnosed in any Norwegian family to date.

Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types.

Allelic loss is a hallmark of tumor suppressor gene (TSG) inactivation. We have allelotyped 29 paired lymphoblastoid and lung cancer cell lines derived from 11 patients with small cell (SCLC) and 18 patients with non-small cell lung carcinomas (NSCLC). Statistical analysis indicated that a threshold of 30% separated non-random allelic loss from the random genetic deletions of malignancy. We have identified non-random allelic loss at 42 of 54 (78%) specific chromosomal regions examined, with 22 regions (52%) common between the two major lung cancer histologic types. There were 3 regions (7%) with allelic loss specific for SCLC and 17 regions (41%) specific for NSCLC. Furthermore, there were significant differences in loss of heterozygosity (LOH) frequencies between NSCLC and SCLC at 13 regions on eight chromosome arms (3p, 5q, 6q, 9p, 10q, 11p, 13q, and 19p). Eight homozygous deletions were present in seven cell lines at four regions, 3p12, 3p14.2, 9p21, and 10q23-25. We have also identified novel sites of chromosomal deletions. In particular, there was frequent loss at 11p13 in SCLC and loss at 6p21.3 and 13q12.3 in NSCLC. In this study, we demonstrate that a) non-random allelic losses in lung cancer involve multiple regions; b) some losses are common to both NSCLC and SCLC subtypes, whereas others are subtype specific; c) there are genetic deletions at novel chromosomal regions; and d) several homozygous deletions have been noted. Our studies demonstrate the usefulness of continuous cell lines for detailed allelotyping, for comparing genetic abnormalities between SCLC and NSCLC, and for identifying homozygous deletions.

The human CAS (cellular apoptosis susceptibility) gene mapping on chromosome 20q13 is amplified in BT474 breast cancer cells and part of aberrant chromosomes in breast and colon cancer cell lines.

The CAS (cellular apoptosis susceptibility) gene is the human homolog of the yeast chromosome segregation gene CSE1. CAS may have a dual function in mammalian cells, one in apoptosis and another in cell proliferation. We have now mapped the CAS gene to chromosome 20q13. This region is known to harbor amplifications that correlate with aggressive breast cancer. Southern hybridizations with a CAS cDNA fragment and fluorescent in situ hybridization (FISH) with a P1 clone containing the CAS gene show elevated copy numbers in one leukemia, three of four colon, and in three of seven breast cancer cell lines. Elevated CAS copy number in CEM leukemia and COLO201 colon cancer cells was attributable to additional copies of chromosome 20. In SW480 and COLO205 colon cancer cells CAS is part of aberrant chromosomes containing large parts of 20q. In breast cancer cells CAS is also part of aberrant 20q chromosomes (MDA-MB-157 and UACC-812) or of additional 20q isochromosome in MDA-MB-134. In MDA-MB361 and BT-474 breast cancer cells CAS is separated from other markers centromeric and telomeric of CAS on 20q. MDA-MB 361 contains one additional copy of CAS, separated from the centromeric 20q control probe. BT-474 cells have up to 12 additional CAS copies that we separated from nearby telomeric and centromeric probes on 20q and that are translocated to abnormal chromosomes.

[Prenatal diagnosis of pulmonary cystic dysplasia associated with a polymorphic variant of chromosome 19. A clinical case]. / Diagnosi prenatale di displasia cistica polmonare associata ad una variante polimorfica del cromosoma 19. Caso clinico.

A case of congenital cystic adenomatoid malformation of the lung diagnosed during pregnancy with, echography in a foetus 19.4 weeks old is reported. The ACP is to be included among the most rare malformations, but even rarer is the prenatal diagnosis. It must to be noted that the previous child of the same couple was also found to be affected by a malformation of the lungs. Through a genetic study of the family it was discovered that both children and the father were carriers of the same morphological chromosomic variation. The authors report the case.

Mapping of transcribed sequences on human chromosome 19.

30 EST/STS have been mapped on human chromosome 19 using a highly specific hncDNA library as a source of transcribed sequences. In addition more than 50 sites constituting 19 families of closely related sequences containing at least one transcribed member each were mapped across the chromosome. Chromosome-19 specific hncDNA clones were hybridized to chromosome 19 cosmids that were previously assembled into contigs covering about 80% of Chr19. The hybridization results were verified by PCR. Such an approach to EST mapping provides information on possible locations of genes as transcribed units of genome and on location of repeated elements used for the priming the hncDNA synthesis. Mapped hncDNA sequences may serve as good starting points for the systematic sequencing of transcribed genomic regions.

Genetics, ethics, and Alzheimer disease.

This article considers the emerging research on Alzheimer disease (AD) genetics in relation to ethical questions surrounding presymptomatic and prenatal genetic testing. Given the rapid advance in AD genetics over the past 8 years, it is likely that the attention of clinicians and ethicists will increasingly turn to genetic issues. After a survey of current genetic knowledge, this article addresses 3 areas of likely ethical concern. While AD genetic screening programs are currently rare and restricted to specific pedigrees, they will become more common in the future. It is, therefore, imperative that society and clinicians begin to consider the ethical issues this raises.