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V V Murty

Publications and source records attributed to V V Murty.

At least 37 records · Page 2Linked to original sources
PubMed1998

Chromosomal amplification is associated with cisplatin resistance of human male germ cell tumors.

Chemotherapy resistance of tumors is an important biological and clinical problem. Studies from many tumor types have indicated that resistance may be based on multiple genetic pathways. Human male germa cell tumors (GCTs) are an especially good model system to study the genetic basis of tumor sensitivity and resistance to chemotherapy. GCTs are exquisitely sensitive to treatment with DNA-damaging drugs such as cisplatin, rarely exhibit TP53 gene mutations, express normal p53 protein, and undergo p53-mediated apoptosis upon drug treatment. A small proportion of tumors (20-30% of metastatic lesions) escape the apoptotic response and result in treatment resistance. We have recently shown (J. Houldsworth, et al., Oncogene, 16: 2345-2359, 1998) that in a subset of such tumors, resistance is linked to TP53 gene mutations. In a further search for genetic mechanisms underlying resistance, we subjected a panel of 17 tumors from relapse-free patients (sensitive) and 17 chemotherapy-resistant tumors to comparative genomic hybridization analysis to identify possible amplified regions (implying amplified/overexpressed genes) associated with resistance. With the exception of 12p11.2-12, high level amplification was not detected in any of the sensitive tumors. We have identified eight amplified regions (1q31-32, 2p23-24, 7q21, 7q31, 9q22, 9q32-34, 15q23-24, and 20q11.2-12) in five resistant tumors, which suggests that chromosomal and, hence, gene amplification may comprise a pathway to drug resistance. Identification of amplified/overexpressed genes at these sites may elucidate new genetic pathways of chemotherapy resistance in GCTs and possibly also in other tumors.

Chromosome Mapping↗
PubMed1998

Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract.

In a search for mutations of the type I transforming growth factor beta receptor (TbetaR-I), we mapped the gene to 9q22 and found a common polymorphism [TbetaR-I(6A)] and a rare variant [TbetaR-I(10A)] of TbetaR-I, causing an in-frame deletion of three alanines and an in-frame insertion of one alanine, respectively, in the receptor's extracellular domain. The biological relevance of the polymorphism TbetaR-I(6A) was investigated. When TbetaR-I(6A) was transiently transfected into TbetaR-I-deficient cells, the growth-inhibitory effects of transforming growth factor beta were restored. TbetaR-I(6A) and TbetaR-I(10A) frequency were assessed in 108 tumor samples and 80 nontumor samples from patients with a diagnosis of cancer, as well as in 118 normal blood donors of comparable ethnic composition. The frequency of TbetaR-I(6A) heterozygotes was fairly similar in normal blood donors (8%), in nontumor DNA of patients with a diagnosis of cancer (10%), and in tumor samples (14%). However, the frequency of TbetaR-I(6A) homozygotes among nontumor (4%) and tumor (8%) samples obtained from patients with a diagnosis of cancer was higher than that predicted by the Hardy-Weinberg law. The clinical and biological significance of TbetaR-I(6A) homozygosity needs to be further investigated.

Acute Disease↗
PubMed1998

Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation.

Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to treatment in 20-30% of metastatic lesions remains to be identified. Unlike other solid tumors, no mutations in the TP53 gene have been identified to date in random panels of GCT specimens, which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or subsequently relapsed and resulted in the death of the patient, we have now identified a subset of tumors to contain TP53 mutations within exons 6-9. A cell line derived from one of these tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin in vitro in comparison to a cell line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene.

Antineoplastic Agents↗
PubMed1998

Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors.

PURPOSE: Teratoma with malignant transformation refers to a form of germ cell tumor in which a somatic teratomatous component becomes morphologically malignant and develops aggressive growth. We evaluated the spectrum of histologies, chromosomal abnormalities and clinical outcome in patients with teratoma with malignant transformation. MATERIALS AND METHODS: We identified 46 patients with germ cell tumor meeting morphologic criteria for malignant transformation. Histology, disease extent and treatment were correlated with survival. Tumors in 12 patients were studied by conventional cytogenetics or molecular genetic techniques for the isochromosome 12p [i(12p)], a marker for germ cell tumor, as well as other chromosomal abnormalities. RESULTS: The site of first detection of malignant transformation occurred in the primary tumor of 21 cases (44%), at a metastatic site in 20 (43%) and in both sites in 5 (10%). Sarcoma was the most frequent histology, identified in 29 patients (63%) with rhabdomyosarcoma the most common subtype. Seventeen tumors (37%) contained a solid tumor histology other than sarcoma, with adenocarcinoma and primitive neuroectodermal tumor as the most common histologies. Four patients with mediastinal germ cell tumor containing sarcoma also had hematological malignancies, including a focus of nonHodgkin's lymphoma in the mediastinal primary tumor (1) and nonlymphocytic leukemia in spleen or bone marrow (3). Patients who had teratoma with malignant transformation components confined to the testis or retroperitoneum completely resected experienced a longer survival than those with distant metastases or incompletely resected tumors (p = 0.003). Chromosomal abnormalities associated with germ cell tumor (i[12p]) were identified in 11 of 12 tumors containing adenocarcinoma, primitive neuroectodermal tumor, sarcoma and leukemia. In addition to i (12p), chromosomal rearrangements characteristic of the transformed histology were detected in 4 tumors. CONCLUSIONS: A variety of nongerm cell histologies, including sarcoma, adenocarcinoma, primitive neuroectodermal tumor and leukemia, may occur in association with germ cell tumor. Chromosomal abnormalities in these tumors include i (12p), reflecting germ cell tumor clonality, as well as chromosomal abnormalities associated with the transformed histology. These tumors do not respond like germ cell tumor to cisplatin-containing chemotherapy regimens. Treatment should be tailored according to that used in standard management of the transformed histology, and surgical resection is the mainstay of therapy.

Adenocarcinoma↗
PubMed1998

Nonsyntenic amplification of MYC with CDK4 and MDM2 in a malignant mixed tumor of salivary gland.

Karyotypic analysis of a metastatic malignant mixed tumor of the salivary gland revealed the presence of double minute chromosomes (dmin), indicative of gene amplification. Comparative genomic hybridization analysis of DNA extracted from the primary and a renal metastasis indicated overt amplification of DNA sequences derived from 8q23-24 and 12q13-15 regions. Subsequent Southern blot analysis of tumor DNA from the metastasis with the use of probes previously mapped to those regions indicated amplification of MYC at 8q23-24 and CDK4 and MDM2 at 12q13-15. Fluorescence in situ hybridization of differentially labeled MYC and MDM2 genes hybridized to tumor metaphase chromosomes revealed an independent nonsyntenic amplification of MYC and MDM2 on dmin in this tumor.

Adult↗
PubMed1998

A genetic perspective of male germ cell tumors.

Adult human male germ cell tumors (GCTs) arise by transformation of germ cells (GCs). The transformed GCs exhibit pluripotentiality to differentiate into embryonic, extra-embryonic, and somatic tissue types, and are highly sensitive to cisplatin-based chemotherapy. Recent investigations into the genetics of GCTs have advanced methods of diagnosis and provided leads to the understanding of molecular basis of transformation, differentiation, and sensitivity/resistance. Cytogenetic and molecular cytogenetic studies have identified multiplication of 12p, manifested in i(12p) or tandem duplication of 12p, as a unique change in GCTs which serves as a diagnostic marker. Ectopic over-expression of cyclin D2, a gene mapped to 12p, as early as in carcinoma in situ identifies a candidate gene in GC transformation. Genetic alterations identified in the tumor suppressor genes deleted in colorectal cancer, retinoblastoma 1 and non-metastatic protein 23 (NME) in GCT suggest that their inactivation play a key role in transformation or differentiation. A number of regions of chromosomal deletion have been identified including those previously known to be deleted in various tumor types and novel candidate tumor suppressor gene sites such as 12q13, 12q22, and 5p15.1-15.2. Identification and characterization of the genes in these sites will provide important clues in understanding the biology of GCT. The molecular studies have also enumerated several possible differentiation controls such as switching of KIT and mast cell growth factor gene expression in a lineage-associated manner, and loss of certain types of genes such as NME in teratomas that may act in a dominant negative fashion in differentiation. The exquisite sensitivity of these tumors to chemotherapy is reflected in their over-expression of wild-type p53 protein and lack of TP53 mutations. These data indicate that multiple genetic events play a role in distinct pathways in the development of GCT, and further elucidation of the underlying genetic and biochemical mechanisms is central to unraveling biology and improving treatment of GCT.

Chromosome Aberrations↗
PubMed1996

Physical mapping of a commonly deleted region, the site of a candidate tumor suppressor gene, at 12q22 in human male germ cell tumors.

A candidate tumor suppressor gene (TSG) site at 12q22 characterized by a high frequency of loss of heterozygosity (LOH) and a homozygous deletion has previously been reported in human male germ cell tumors (GCTs). In a detailed deletion mapping analysis of 67 normal-tumor DNAs utilizing 20 polymorphic markers mapped to 12q22-q24, we identified the limits of the minimal region of deletion at 12q22 between D12S377 (proximal) and D12S296 (distal). We have constructed a YAC contig map of a 3-cM region of this band between the proximal marker D12S101 and the distal marker D12S346, which contained the minimal region of deletion in GCTs. The map is composed of 53 overlapping YACs and 3 cosmids onto which 25 polymorphic and nonpolymorphic sequence-tagged sites (STSs) were placed in a unique order. The size of the minimal region of deletion was approximately 2 Mb from overlapping, nonchimeric YACs that spanned the region. We also developed a radiation hybrid (RH) map of the region between D12S101 and D12S346 containing 17 loci. The consensus order developed by RH mapping is in good agreement with the YAC STS-content map order. The RH map estimated the distance between D12S101 and D12S346 to be 246 cR8000 and the minimal region of deletion to be 141 cR8000. In addition, four genes that were previously mapped to 12q22 have been excluded as candidate genes. The leads gained from the deletion mapping and physical maps should expedite the isolation and characterization of the TSG at 12q22.

Chromosomes, Human, Pair 12↗
PubMed1996

Deletion mapping identifies loss of heterozygosity at 5p15.1-15.2, 5q11 and 5q34-35 in human male germ cell tumors.

Cytogenetic and loss of heterozygosity (LOH) studies of chromosome 5 in male germ cell tumors (GCTs) previously reported suggested the presence of one or more tumor suppressor genes (TSGs) on this chromosome which may play a role in the development of these tumors. In an attempt to further characterize allelic deletions on chromosome 5, we performed a detailed deletion mapping utilizing 66 normal-tumor DNAs from male GCTs assaying 24 polymorphic markers mapped to both the short and long arms. Thirty-seven (56%) tumors exhibited LOH at one or more loci. Loss of one allele at all informative loci was found in 15 of 37 (40.5%) cases suggesting monosomy of chromosome 5. The pattern of LOH in the remaining 22 (59.5%) tumors revealed regional losses identifying three common sites of deletions at 5p15.1-15.2, 5q11, and 5q34-35, respectively. The distribution of allelic deletions was found to be similar in all histologic subtypes with predominance of monosomy in teratomas. Thus, the present study revealed 2 types of chromosome 5 abnormalities in male GCTs, genetic monosomy and regional deletion, the latter identifying three novel sites of candidate TSGs. These data suggest that loss of genetic information on chromosome 5 plays an important role in male GCT development.

Chromosome Deletion↗
PubMed1995

Chromosomal assignment of human ID1 and ID2 genes.

The Id (inhibitor of DNA binding) proteins regulate transcription during development by interacting with transcription factors. Three human genes, ID1, ID2, and ID3, have been identified that belong to this family of transcription regulators. We show, by somatic cell hybridization and fluorescence in situ hybridization experiments, that ID1 and ID2 are localized at 20q11 and 2p25, respectively.

Blotting, Southern↗
PubMed1995

p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14)(q13;q32).

The t(11;14)(q13;q32) translocation, which juxtaposes the BCL1 oncogene with the Ig heavy chain locus, has been associated with an uncommon subtype of non-Hodgkin's lymphoma (NHL) termed mantle cell lymphoma (MCL). To date, no molecular marker that serves as an indicator of tumor progression or clinical prognosis has been described for NHLs with this translocation. We examined a panel of NHLs with t(11;14) for overexpression of p53 and correlated the results with single-strand conformation polymorphism (SSCP) analysis, karyotypic features, and clinical course. NHLs with t(11;14) were identified from 30 patients. The diagnosis was MCL for 23 of 30, small lymphocytic lymphoma for 4 of 30, and diffuse large-cell lymphoma for 3 of 30 cases. The results of immunohistochemistry analysis using a monoclonal anti-p53 antibody on paraffin-embedded specimens were compared with the SSCP data, the tumor karyotypes, and clinical course of each patient. DNA sequencing of exons was performed on cases that showed conformational changes by SSCP analysis. NHLs from 5 of 23 patients with MCL were positive for p53 overexpression. Deletions of chromosome 17p were identified in 2 of 30 cases, both of which were MCLs showing p53 overexpression. Two of the five MCLs with p53 overexpression showed evidence for TP53 mutations. None of the 18 MCLs negative for p53 overexpression showed conformational changes by SSCP. For these 18 patients with MCLs that did not overexpress p53, the median survival was 63 months, compared with 12 months for the 5 patients with MCLs positive for p53 overexpression (P < .001). These results suggest that p53 overexpression in MCL with t(11;14)(q13;q32) may serve as a marker of poor prognosis.

Adult↗
PubMed1995

Genetic alterations at 5p15: a potential marker for progression of precancerous lesions of the uterine cervix.

BACKGROUND: Development of uterine cervical cancer is preceded by preneoplastic proliferative changes in the cervical epithelium called "intra-epithelial neoplasia" or "dysplasia." The genetic basis of the origin and progression of such preneoplastic lesions is not known. By analysis of carcinomas for loss of constitutional heterozygosity (LOH), we have previously shown a high frequency of allelic loss in the short arm of chromosome 5 (5p), suggesting loss of a candidate tumor suppressor gene located in 5p and associated with the development of this tumor. PURPOSE: To further understand the role of genetic alterations that affect 5p in cervical carcinogenesis, we evaluated the status of microsatellite polymorphisms at five loci mapped to 5p14-ter in precancerous and cancerous lesions. METHODS: Biopsy specimens from two groups of patients were analyzed for genetic alterations affecting 5p. One group comprised 14 cases of precancerous lesions (i.e., dysplasias) and five cases of carcinoma in situ (CIS); the second group comprised 46 previously untreated patients with invasive carcinoma. Tumor and normal DNAs were analyzed by polymerase chain reaction for genetic losses and instability at five polymorphic microsatellite loci (D5S392, D5S406, D5S208, D5S117, and D5S432) mapped to 5p. RESULTS: LOH was observed in 25 (55.6%) of 45 informative invasive carcinomas, one (20%) of five cases of CIS, and three (21%) of 14 precancerous lesions. Among the loci tested, D5S406 (5p15.1-15.2) exhibited LOH in 12 (48%) of 25 invasive carcinomas, one (33%) of three cases of CIS, and three (60%) of five precancerous lesions, suggesting this to be the site in 5p of the novel candidate tumor suppressor gene. In addition, replication error-type alterations were noted in the 5p14-ter region in six (13%) of 46 invasive carcinomas, two (40%) of five cases of CIS, and three (21%) of 14 precancerous lesions. Instability affected D5S406 in eight (66.7%) of 12 instances that showed microsatellite instability. CONCLUSION: These observations suggest that allelic loss and microsatellite instability in the region of D5S406 may play a role early in the development of cervical carcinoma and identify the site of a candidate tumor suppressor gene. These genetic markers (allelic loss and microsatellite instability) may also define CIS and precancerous lesions at high risk for progression to invasive cancer. IMPLICATIONS: The future molecular cloning of the candidate tumor suppressor gene at 5p15.1-15.2 may provide new insights into the genetic mechanisms of cervical carcinogenesis. Analysis and clinical follow-up of a large cohort of prospectively ascertained cases of precancerous lesions would help to validate the usefulness of these markers.

Biomarkers, Tumor↗
PubMed1995

Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors.

Deletion of 9p21-22 is a common genetic alteration in dysplastic, in situ, and invasive head and neck squamous cell carcinoma (HNSCC). However, a candidate tumor suppressor gene (TSG) at this site has thus far not been identified in HNSCC. We report homozygous deletion of the recently identified multiple tumor suppressor I (MTSI)/cyclin-dependent kinase-4-inhibitor (CDKN2) gene mapped to 9p21, which encodes the p16 protein, a regulator of cyclin-dependent kinase 4, in six of 16 HNSCC cell lines. We also show absence of the CDKN2 mRNA in all cell lines with CDKN2 deletion as well as in an additional two cell lines without deletion. Overall, we have identified 9p abnormalities in 12 of 16 (75%) cell lines, at least nine of which involved CDKN2. We further demonstrate that the CDKN2 deletion in HNSCC is located within a previously described region of allelic loss between D9S171 and IFNW, which spans a 4 cM region of 9p. However, examination of 36 primary tumors revealed genetic alterations in only seven of 36 (19%) tumors. These results suggest that genetic alterations at CDKN2 are frequent in HNSCC cell lines, but the role of this gene in primary tumors is less compelling. CDKN2 does not appear to be the only TSG on 9p21 in HNSCC, and our results suggest that another region of deletion exists proximal to the IFNW locus.

Carcinoma, Squamous Cell↗
PubMed1994

Loss of heterozygosity identifies multiple sites of allelic deletions on chromosome 1 in human male germ cell tumors.

Cytogenetic analysis of human male germ cell tumors (GCTs) and derived cell lines revealed frequent deletions and rearrangements of chromosome 1. However, no detailed molecular analysis of these aberrations has thus far been performed. We undertook loss of heterozygosity (LOH) analysis utilizing a panel of 48 GCTs at 22 subregionally mapped polymorphic loci on both arms of chromosome 1. Eight probes, for which precise mapping data were unavailable, were subregionally mapped to specific regions by fluorescence in situ hybridization. Allelic losses were observed in 46% of cases on 1p and in 23% of cases on 1q. Teratomas showed higher frequency of allelic losses compared to embryonal carcinomas, yolk sac tumors, and seminomas, consistent with the results of our previous allelotype analysis, which showed overall higher genetic loss in teratomas compared to embryonal carcinomas. Our LOH study of chromosome 1 identified 4 sites of frequent deletions, 3 in the short arm (1p13, 1p22, and 1p31.3-32.2) and 1 in the long arm (1q32). Of these, 38.5% LOH at 1p22 (D1S16) identifies the site of a novel candidate tumor suppressor gene (TSG), possibly associated with GCTs. LOH at the remaining sites (1p13, 1p31.3-32.2, and 1q32) has also been reported in breast carcinomas, suggesting the involvement of TSGs common to both tumor types.

Alleles↗
PubMed1994

TP53 gene mutations and CCND1 gene amplification in head and neck squamous cell carcinoma cell lines.

Mutations of the tumor-suppressor gene TP53 and amplification of CCND1 gene have been reported to occur frequently in head and neck squamous cell carcinomas (HNSQCC). In experimental systems, TP53 mutations have been shown to lead to genomic instability, including an increased propensity for gene amplification. We have examined 16 HNSQCC cell lines for the association between TP53 over-expression/mutation and CCND1 amplification. p53 over-expression was detected in 50% of the cell lines by immunohistochemistry using the monoclonal antibody (MAb) PAb1801. TP53 mutations were also detected in 50% of the cell lines by analysis of single-strand conformation polymorphism (SSCP) and DNA sequencing of exons 4 through 9. Six cell lines showed TP53 mutations and over-expression of the protein, 2 cell lines showed TP53 mutations but no p53 expression, and 2 cell lines showed over-expression of p53 protein but no TP53 gene mutations. CCND1 amplification was found in 38% of the cell lines by Southern blot analysis. Only 1 cell line showed both TP53 mutation and CCND1 amplification, whereas 7 of 8 cell lines with TP53 mutations had no CCND1 amplification. pRb expression was detected by Western blot analysis, and the level of pRb did not correlate with either CCND1 amplification or TP53 mutation. Our findings suggest that TP53 mutation and CCND1 amplification are common genetic alterations in HNSQCC and that the occurrence of either genetic event may be sufficient to abrogate normal cell cycle control.

Carcinoma, Squamous Cell↗
PubMed1994

Allelotype analysis of cervical carcinoma.

To identify the genetic events which may play a role in the development of cervical carcinoma, we performed a detailed allelotype analysis utilizing DNA from 53 primary tumors and corresponding normal cells and 57 polymorphic probes mapped to each of the chromosomal arms, excluding the short arms of the acrocentric chromosomes. Loss of heterozygosity (LOH) of > 25% was observed at sites on 11 chromosomal arms, which included 1q (26%), 3p (35%), 3q (31%), 4q (46%), 5p (53%), 5q (38%), 6p (28%), 10q (28%), 11p (42%), 18p (38%), and Xq (26%). The most frequent LOH was noted on 4q (ADH3) and 5p (D5S19), suggesting that loss of candidate tumor suppressor genes on these chromosomal arms may play a role in the development of cervical carcinoma. The two sites of deletions identified on 5p and Xq represent novel candidate tumor suppressor gene sites which have so far not been reported in any other tumor type. Human papilloma virus status did not correlate with any of the sites which showed frequent LOH. TP53 mutation analysis by single-strand conformation polymorphism analysis was performed in 17 tumors that either showed 17p deletions (TP53, D17S5, or D17S28) or were human papilloma virus negative. One of the 7 human papilloma virus-negative tumors, which also showed LOH at the D17S28 locus, had a mutation in exon 5. This study represents the first comprehensive genetic analysis of this cancer and identifies several novel features of significance to genetic etiology of cervical carcinoma.

Adult↗
PubMed1994

Characterization of the promoter region of the gene for the rat neutral and basic amino acid transporter and chromosomal localization of the human gene.

The promoter region of the rat kidney neutral and basic amino acid transporter (NBAT) gene has been isolated and sequenced. The major transcription initiation site was mapped by primer extension. The entire promoter region and a set of 5' deletions within it were expressed at a high level in LLC-PK1 cells using the luciferase indicator gene. Positive and negative regulatory elements in the promoter region were observed. A human genomic clone of the transporter was also obtained and was used to localize the NBAT gene at the p21 region of chromosome 2.

Amino Acid Sequence↗
PubMed1994

Replication error-type genetic instability at 1q42-43 in human male germ cell tumors.

The replication error phenotype, recognized as microsatellite sequence alterations, has recently been suggested to be associated with hereditary nonpolyposis colorectal cancer and other types of sporadic tumors. We examined paired tumor-normal DNAs from 69 human male germ cell tumors for somatic instability at the 1q42-43 region. Analysis of a variable number of tandem repeats marker (D1S74) and 3 (CA)n type microsatellite loci (D1S235, D1S180, and angiotensinogen) revealed genetic alterations in tumor DNAs of 26 (38.2%) cases. The changes observed comprised rearrangements with D1S74 detected by Southern blot analysis in 4 of 55 (7%) cases; replication error-type alterations with D1S235, D1S180, and angiotensinogen in 12 of 66 (18.2%) cases; and loss of heterozygosity in 12 of 67 (17.9%) cases with the same probes. The microsatellite sequence alterations were more common in histological subsets other than teratomas, while the loss of heterozygosity was significantly more frequent in teratomas compared to other histologies. These results suggest that microsatellite instability and loss of heterozygosity at 1q42-43 may be unrelated genetic events which may play a role in germ cell tumor development.

Chromosomes, Human, Pair 1↗