Biomedical subjects

P Lichter

Publications and source records attributed to P Lichter.

At least 19 recordsLinked to original sources

PubMed2006

Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays.

To identify candidate genes relevant for prostate tumour prognosis and progression, we performed an exhaustive gene search in seven previously described genomic-profiling studies of 161 prostate tumours, and four expression profiling studies of 61 tumours. From the resulting list of candidate genes, six were selected for protein-expression analysis based on the availability of antibodies applicable to paraffinised tissue: fatty acid synthase (FASN), MYC, beta-adrenergic receptor kinase 1 (BARK1, GRK2) the catalytic subunits of protein phosphatases PP1alpha (PPP1CA) and PP2A (PPP2CB) and metastasis suppressor NM23-H1. These candidates were analysed by immunohistochemistry (IHC) on a tissue microarray containing 651 cores of primary prostate cancer samples and benign prostatic hyperplasias (BPH) from 175 patients. In univariate analysis, expression of PP1alpha (P=0.001) was found to strongly correlate with Gleason score. MYC immunostaining negatively correlated with both pT-stage and Gleason score (P<0.001 each) in univariate as well as in multivariate analysis. Furthermore, a subgroup of patients with high Gleason scores was characterised by a complete loss of BARK1 protein (P=0.023). In conclusion, our study revealed novel molecular markers of potential diagnostic and therapeutic relevance for prostate carcinoma.

Biomarkers, Tumor↗

PubMed2006

Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas.

The molecular pathogenesis of pleomorphic xanthoastrocytoma (PXA), a rare astrocytic brain tumor with a relatively favorable prognosis, is still poorly understood. We characterized 50 PXAs by comparative genomic hybridization (CGH) and found the most common imbalance to be loss on chromosome 9 in 50% of tumors. Other recurrent losses affected chromosomes 17 (10%), 8, 18, 22 (4% each). Recurrent gains were identified on chromosomes X (16%), 7, 9q, 20 (8% each), 4, 5, 19 (4% each). Two tumors demonstrated amplifications mapping to 2p23-p25, 4p15, 12q13, 12q21, 21q21 and 21q22. Analysis of 10 PXAs with available high molecular weight DNA by high-resolution array-based CGH indicated homozygous 9p21.3 deletions involving the CDKN2A/p14(ARF)/CDKN2B loci in six tumors (60%). Interphase fluorescence in situ hybridization to tissue sections confirmed the presence of tumor cells with homozygous 9p21.3 deletions. Mutational analysis of candidate genes on 9q, PTCH and TSC1, revealed no mutations in PXAs with 9q loss and no evidence of TSC1 promoter methylation. However, PXAs consistently showed low TSC1 transcript levels. Taken together, our study identifies loss of chromosome 9 as the most common chromosomal imbalance in PXAs and suggests important roles for homozygous CDKN2A/p14(ARF)/CDKN2B deletion as well as low TSC1 mRNA expression in these tumors.

Adolescent↗

PubMed2006

Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development.

Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well.

Animals↗

PubMed2006

Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components.

Desmoplastic medulloblastoma (DMB) is a malignant cerebellar tumour composed of two distinct tissue components, pale islands and desmoplastic areas. Previous studies revealed mutations in genes encoding members of the sonic hedgehog pathway, including PTCH, SMOH and SUFUH in DMBs. However, little is known about other genomic aberrations. We performed comparative genomic hybridization (CGH) analysis of 22 sporadic DMBs and identified chromosomal imbalances in 20 tumours (91%; mean, 4.9 imbalances/tumour). Recurrent chromosomal gains were found on chromosomes 3, 9 (six tumours each), 20, 22 (five tumours each), 2, 6, 7, 17 (four tumours each) and 1 (three tumours). Recurrent losses involved chromosomes X (eight tumours), Y (six of eleven tumours from male patients), 9, 12 (four tumours each), as well as 10, 13 and 17 (three tumours each). Four tumours demonstrated high-level amplifications involving sequences from 1p22, 5p15, 9p, 12p13, 13q33-q34 and 17q22-q24, respectively. Further analysis of the 9p and 17q22-q24 amplicons by array-based CGH (matrix-CGH) and candidate gene analyses revealed amplification of JMJD2C at 9p24 in one DMB and amplification of RPS6KB1, APPBP2, PPM1D and BCAS3 from 17q23 in three DMBs. Among the 17q23 genes, RPS6KB1 showed markedly elevated transcript levels as compared to normal cerebellum in five of six DMBs and four of five classic medulloblastomas investigated. Finally, CGH analysis of microdissected pale islands and desmoplastic areas showed common chromosomal imbalances in five of six informative tumours. In summary, we have identified several novel genetic alterations in DMBs and provide genetic evidence for a monoclonal origin of their different tissue components.

Base Sequence↗

PubMed2005

Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC).

Overrepresentation of chromosomal bands 3q25-q29 has been associated with shortened disease-specific survival in head and neck squamous cell carcinoma (HNSCC). To assess the prevalence of copy number gains (>4 signals per cell) and high-level amplifications (>8 signals per cell) from putative oncogenes in this chromosomal region (CCNL1, SNO, PIK3CA, TP73L), tissue microarray analysis was applied on 280 HNSCCs by fluorescence in situ hybridization. Overall frequency of additional copy numbers was 34.3% for CCNL1, 31.8% for SNO, 39.0% for PIK3CA and 38.3% for TP73L, respectively. In general, gains were more frequently detected in stage IV compared to stage I-III tumours. Performing multivariate logistic regression analysis, a significant association of CCNL1 gains and the presence of lymph node metastases was found, which was independent of anatomical site and T-stage of the primary tumour (P=0.049). Site-specific subgroup analysis further showed that copy number gains of CCNL1 and SNO occurred more frequently in oral carcinomas in advanced clinical stages as compared to N0 oral lesions (CCNL1: P=0.03; SNO: P=0.03). Finally, Kaplan-Meier analysis revealed that high-level amplifications of CCNL1 correlated with shorter overall survival of the patients. Our results indicate that CCNL1 plays a critical role in the loco-regional progression of HNSCC and may serve as an indicator for occult advanced tumour stages.

Biomarkers, Tumor↗

PubMed2005

Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL).

The pathogenic role of trisomy 12 in chronic lymphocytic leukemia (CLL) remains unresolved, but recently an upregulated RNA expression level has been observed for chromosome 12 candidate genes. In the current study, the protein expression of chromosome 12 candidate genes was characterized by comparing CLL cases with (n=58) or without (n=16) trisomy 12, CD19+-B-cells and cell lines (JVM-2, EHEB, JURKAT). Immunoblotting was performed to quantify the levels of AID, APAF-1, ARF3, CCND2, CDK2, CKD4, GLI, MDM-2, p27, Smac/DIABLO and STAT6 (signal transducer and activator of transcription 6). The cell lines showed distinct expression patterns for CCND2, MDM-2, p27, Smac/DIABLO and STAT6, and displayed higher levels of CDK2 and CDK4 than the CLL cases. JURKAT and the CLL cases expressed uniformly high levels of p27, but low levels of CCND2. AID expression in the CLL cases was weak with slight variations regardless of the subgroup affiliation. The expression of the investigated proteins was independent of the trisomy 12 status as well as of the VH mutation status. The comparison of CD19+-B-cells with CLL revealed higher protein levels in CLL for CDK4, p27, Smac/DIABLO and STAT6. Further studies including protein expression experiments in genetic high-risk subgroups of CLL have to elucidate whether these proteins qualify as candidates for targeted CLL therapies.

Antigens, CD19↗

PubMed2003

DNA microarray analysis in malignant lymphomas.

Recently, DNA microarray technology has opened new avenues for the understanding of lymphomas. By hybridization of cDNA to arrays containing >10,000 different DNA fragments, this approach allows the simultaneous evaluation of the mRNA expression of thousands of genes in a single experiment. Using sophisticated bioinformatic tools, the huge amount of raw data can be clustered resulting in (1) tumor subclassification, (2) identification of pathogenetically relevant genes, or (3) biological predictors for the clinical course. This approach already has provided novel insights into different entities of B-cell non-Hodgkin's lymphomas. Genomic DNA chip hybridization (matrix-CGH) is a complementary approach focussing on genomic aberrations. In this review, we discuss the impact of this new technology both with regard to methodological aspects as well as to novel findings influencing our understanding of lymphomas.

Gene Expression Profiling↗

PubMed2003

[A new dimension of DNA analysis: genomic profiling by matrix CGH].

Analysis of genetic alterations in tumor cells represent a first step to understand the molecular mechanism of cancer etiology and development. Due to the progress in genome research, it is feasible to assess the complexity of genomic changes on a large scale. Protocols for gene expression profiling using cDNA arrays have been developed allowing to test the activity of almost all human genes in tumor cells. Another important approach is matrix-CGH which was recently developed to assess gains and losses on the genomic level with high resolution. This method not only allows to narrow down the position of novel oncogenes or tumor suppressor-genes but also contributes to a refinement of tumor classifications. Since matrix-CGH can be performed under highly standardized conditions in a fully automatized way, it is suited for diagnostics in clinical laboratories.

Chromosome Aberrations↗

PubMed2002

[Opportunities and chances for tissue chip microarrays in head and neck surgery. A novel technique for the rapid evaluation of potentially novel biomarkers].

Oral squamous cell carcinomas (OSCC) are malignant tumors with a poor prognosis and low long-term survival rates, even when using modern adjuvant and neoadjuvant therapy forms in addition to surgery. For the clinical estimation of each tumor, it is necessary to define stage-dependent molecular and/or cellular parameters as it is known that OSCC develop along a multistep pathway including the loss of tumor suppressor genes and the amplification of oncogenes which result in changes in protein expression. In order to establish a reliable pattern of molecular and cellular biomarkers, a large number of tumor specimens from different stages of the disease need to be analysed. In this study, biopsies of a collective of 293 OSCC in different stages were screened with the novel technique of tissue chip microarrays by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). FISH-analysis was performed on the oncogene cyclin D1 and IHC-analysis on the proteins cyclin D1, p53, p16, cdk4, bcl2, mdm2 and rb. Tissue chip technology was shown to facilitate rapid screening for molecular and cellular alterations in different stages of OSCC and revealed reliable and reproducible results that may allow the definition of a multistep pathway model for tumor progression in OSCC.

Aged↗

PubMed2002

Topological organization of the MYC/IGK locus in Burkitt's lymphoma cells assessed by nuclear halo preparations.

In Burkitt's lymphoma (BL) cells characteristic chromosomal translocations juxtapose the MYC oncogene to one of the three immunoglobulin (IG) gene loci. This results in deregulation of MYC expression through IG gene enhancer elements. As enhancers and MYC promoters can be as much as several hundred kilobases apart, long-distance effects are to be postulated, which affect chromatin organization. Since transcriptionally active and inactive sequences can be distinguished based on their localization in nuclear halo preparations, we used this technique to assess the topology of wild-type and translocated MYC and IGK genes. Following visualization of these genes by fluorescence in situ hybridization, the signal distribution was determined in nuclear halo structures of human monocytes and the BL-derived cell line LY66. MYC signals derived from the non-translocated chromosome 8 were found equally distributed between the residual nucleus and the surrounding DNA halo. In contrast, the activated MYC and IGK genes on the translocated chromosome in LY66 cells were associated with the residual nucleus in 78 and 88% of cases, respectively. In LY66 cells, attachment to the residual nucleus was restricted to a DNA segment 30 to 50 kb downstream of MYC, while in monocytes it was dispersed over 80 kb around the MYC gene. These findings indicate a specific chromatin organization for the activated MYC locus. Distance measurements between MYC and IGK signals revealed shorter values than expected from their linear distance (325 kb), indicating a back folding of the DNA backbone. Thus, there is strong evidence for a specific topological organization, which is functionally related to the MYC activation status with the specific folding of the DNA strand likely reflecting maintenance of a spatial interaction between IGK enhancer and MYC promoter elements.

Burkitt Lymphoma↗

PubMed2002

Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course.

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40-50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of CLL cases. Genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. For the most frequent aberration, the deletion 13q14, candidate genes have been isolated. Genetic subgroups with distinct clinical features have been identified. 11q deletion is associated with marked lymphadenopathy and rapid disease progression. 17p deletion predicts for treatment failure with alkylating agents, as well as fludarabine and short survival times. In multivariate analysis 11q and 17p deletions provided independent prognostic information. Recently, another important issue of genetic risk classification in CLL was identified with the mutation status of the immunoglobulin variable heavy chain genes (V(H)). CLL cases with unmutated V(H) show more rapid disease progression and shorter survival times. Whether CD38 expression can serve as a surrogate marker for V(H) mutation status is currently discussed controversially. V(H) mutation status and genomic abnormalities, such as 17p and 11q deletion, have recently been shown to be related to each other, but were of independent prognostic information in multivariate analysis. Moreover, genomic aberrations and V(H) mutation status appear to give prognostic information irrespective of the clinical stage and may therefore allow a risk assessment for individual patients early in the course of their disease.

Chromosome Aberrations↗

PubMed2001

Nuclear envelope and chromatin compositional differences comparing undifferentiated and retinoic acid- and phorbol ester-treated HL-60 cells.

The human leukemic cell line (HL-60) can be induced to differentiate in vitro to granulocytic form with retinoic acid (RA), or to monocytic/macrophage form with phorbol ester (TPA). The granulocytic form acquires nuclear lobulation, nuclear envelope-limited chromatin sheets (ELCS), and cytoskeletal polarization, none of which are acquired following treatment with TPA. Immunoblotting analyses and capillary zone electrophoresis demonstrated that following RA treatment: lamins A/C and B1, and vimentin decreased to negligible amounts; LAP2 beta, lamin B2 and emerin remained essentially unchanged; lamin B receptor (LBR) increased markedly; histone subtypes H1.4 and 1.5 exhibited dephosphorylation. Following TPA treatment: lamins A/C and B1, B2 and vimentin increased in amount; LAP2 beta and emerin remained essentially unchanged; LBR increased markedly; histone subtypes H1.4 and 1.5 exhibited dephosphorylation. Emerin, which was cytoplasmic in undifferentiated or granulocytic cells, localized into the nuclear envelope following TPA. Normal human granulocytes revealed compositional differences compared to granulocytic forms of HL-60, namely increased vimentin and appearance of histone subtype H1.3. A working hypothesis for nuclear lobulation postulates a combination of: increased nuclear envelope deformability due to lamins A/C and B1 deficiency; an increase in nuclear surface area/volume; an increase in chromatin-nuclear envelope interactions.

Cell Compartmentation↗

PubMed2001

B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions.

Deletions in chromosomal band 13q14.3 occur in >50% of B-cell chronic lymphocytic leukemias (B-CLL) and mantle cell lymphoma, indicating the localization of a tumor suppressor gene involved in the pathomechanism of these diseases. Within a 400 kb recurrently deleted segment at least two minimally deleted subregions had been reported. For the two genes residing in the proximal subregion, initially named LEU1 and LEU2, a pathogenic role has not yet been established. We report here that LEU1 is only a small portion of a large gene, which spans all previously reported critical subregions including the distal subregion. This gene, designated B-cell neoplasia-associated gene with multiple splicing (BCMS), is composed of at least 50 exons spanning >or=560 kb of genomic DNA and is expressed in more than 20 RNA splicing variants. While tissue-specific expression of RNA variants was observed, there was no evidence for the expression of a variant specific for B-CLL. Sequence analysis of the RNA variants suggests that BCMS transcripts belong to the group of non-coding RNAs. The alignment of the gene with all critical subregions provides a strong argument for BCMS being the most likely candidate for the tumor suppressor gene in 13q14 involved in the leukemogenesis of B-CLL. Due to the limited understanding of functional RNAs, however, it remains difficult to prove the pathogenic role of BCMS.

Alternative Splicing↗

PubMed2001

Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18.

We have previously reported that losses of genomic material from the long arm of chromosome 18 are frequent in atypical and anaplastic meningiomas but rare in benign meningiomas. In the present study, we have investigated a series of 37 meningiomas for mutation and expression of 4 tumor suppressor genes (MADH2, MADH4, APM-1 and DCC) located at 18q21. Comparative genomic hybridization or loss of heterozygosity analysis showed losses on chromosome 18 that included sequences from 18q21 in 15 of 37 tumors. Mutation analysis of APM-1 revealed a missense mutation (c. 1819G>A: G607S) in 1 atypical meningioma. None of the tumors showed mutations of MADH2 and MADH4 or loss of detectable transcripts from MADH2, MADH4, APM-1 and DCC. In contrast to human brain tissue, normal leptomeninges and meningiomas showed preferential expression of a DCC splice variant lacking 60 base pairs from exon 17. Taken together, our data do not support a significant role for MADH2, MADH4, APM-1 and DCC alterations in the pathogenesis of meningiomas. The targeted gene that is inactivated in most meningiomas with 18q losses remains to be identified.

Adiponectin↗

PubMed2001

CDNA microarray gene expression analysis of B-cell chronic lymphocytic leukemia proposes potential new prognostic markers involved in lymphocyte trafficking.

Human cancer is characterized by complex molecular perturbations leading to variable clinical behavior, often even in single-disease entities. We performed a feasibility study systematically comparing large-scale gene expression profiles with clinical features in human B-cell chronic lymphocytic leukemia (B-CLL). cDNA microarrays were employed to determine the expression levels of 1,024 selected genes in 54 peripheral blood lymphocyte samples obtained from patients with B-CLL. Statistical analyses were applied to correlate the expression profiles with a number of clinical parameters including patient survival and disease staging. We were able to identify genes whose expression levels significantly correlated with patient survival and/or with clinical staging. Most of these genes code either for cell adhesion molecules (L-selectin, integrin-beta2) or for factors inducing cell adhesion molecules (IL-1beta, IL-8, EGR1), suggesting that prognosis of this disease may be related to a defect in lymphocyte trafficking. This report demonstrates the feasibility of a systematic integration of large-scale gene expression profiles with clinical data as a general approach for dissecting human diseases.

Adult↗

PubMed2001

Loss of the Y chromosome is a frequent chromosomal imbalance in pancreatic cancer and allows differentiation to chronic pancreatitis.

In a study for the identification of genomic alterations in pancreatic cancer, representational difference analysis was used and led to the isolation of 2 distinct fragments, deleted on the Y chromosome in the xenografted tumor DNA of a male patient with an adenocarcinoma of the pancreas. Loss of Y chromosomal material was further studied in 11 pancreatic cancer cell lines of male origin, using PCR amplification of 5 sequence tagged sites (STSs) distributed along the Y chromosome; 8/11 cell lines exhibited a complete loss of the Y chromosome and 3 had deletions. To examine the status of the Y chromosome in situ, interphase FISH analysis was performed on paraffin sections from pancreatic carcinoma (n=7) and chronic pancreatitis (n=7) tissues, and the loss of Y-chromosomal STS-markers was studied in 6 xenograft tumors obtained from male pancreatic cancer patients. This analysis revealed that a loss of the Y chromosome occurs in vivo in primary pancreatic tumor cells, whereas the Y chromosome was intact in chronic pancreatitis. Our data suggest that loss of Y is a frequent event occurring in male pancreatic tumors. Although there is no evidence for a functional implication of Y chromosome loss, it effectively differentiates between a malignant and a benign condition as e.g. chronic pancreatitis. Thus, this genetic alteration may be of diagnostic use.

Animals↗

PubMed2001

Chromosomal imbalances associated with response to chemotherapy and cytotoxic cytokines in human malignant glioma cell lines.

The median survival for human malignant glioma patients treated with neurosurgery and postoperative radiotherapy does not exceed one year. Only a minority of patients benefit from adjuvant chemotherapy. It was the aim of our study to determine which genomic alterations in malignant gliomas modulate the sensitivity to chemotherapy or cytotoxic cytokines such as CD95 ligand (CD95L) or Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Therefore, we analyzed 12 human malignant glioma cell lines for chromosomal gains and losses by comparative genomic hybridization (CGH). The gains most commonly identified were on chromosomes 7q, 19, 1, and 20q, whereas the most frequent losses were on 13q, 11q, 18q, and 4q. By comparison with previously published data on this panel of glioma cell lines1112, we defined candidate regions which may carry genes responsible for sensitivity to chemotherapy or cytotoxic cytokines. All but one of the chromosomal regions associated with response to chemotherapy, i.e. 1p12, 3p21, 11p11.2-p13, 12q23, 17p11. 2-p13, were different from those associated with response to cytotoxic cytokines, i.e. lp12, 1q22, 12q12-q21. Genomic regions known to harbor major candidate genes, including genes encoding death ligands, death receptors, caspases and BCL-2 family proteins, were not found to be imbalanced. In addition, we identified 5q13-q14, 5q34, 10p11.2, 9q21-q34 as genomic regions associated with the proliferative activity of malignant glioma cell lines. Cell lines with gain on proximal 5q, where CCNB1 and CCNH reside, showed an increased growth rate, suggesting that cyclins activating cdc2, the dominant G2/M phase kinase, may play a role in glioma tumorigenes.

Apoptosis↗

PubMed2001

Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line.

Primary mediastinal B-cell lymphoma (MBL) is an aggressive Non-Hodgkin's Lymphoma, which has been recognized as a distinct disease entity. We performed a comprehensive molecular cytogenetic study analyzing 43 MBLs. By comparative genomic hybridization (CGH), the most common aberrations were gains of chromosome arms 9p and Xq, which were present in 56% and 40% of cases, respectively. Based on the limited resolution of CGH, this technique may underestimate the real incidence of aberrations. Therefore, we also did an interphase cytogenetic study with eight DNA probes mapping to chromosome regions frequently altered in B-cell lymphomas. With this approach, both 9p and Xq gains were found in more than 70% of cases (75% and 87%, respectively). The findings were compared with results obtained in 308 other B-cell lymphomas. Gains in 9p were identified in only six of the 308 cases, and only one of these lymphomas with 9p gains was not primarily extranodal in origin (P < 10-(20) for CGH data and P < 10-(11) for fluorescence in situ hybridization data). We also present a novel MBL cell line, MedB-1, which carries the genetic aberrations characteristic of this entity.

Adolescent↗