Antisense RNA to the putative tumor suppressor gene "deleted in colorectal cancer" transforms fibroblasts.
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Animals↗
Biomedical subjects
K R Cho
Publications and source records attributed to K R Cho.
Genetic alterations in the adenoma--carcinoma sequence.
Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate, ultimately producing the neoplastic phenotype. A model was proposed to explain the genetic basis of colorectal neoplasia that included several salient features. First, colorectal tumors appear to occur as a result of the mutational activation of oncogenes coupled with the inactivation of tumor-suppressor genes. Second, mutations in at least four or five genes are required to produce a malignant tumor. Third, although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their chronologic order of appearance, is responsible for determining the tumor's biologic properties. Several different genetic alterations were identified that occur during colorectal tumorigenesis. Activational mutation of the ras oncogene was found in approximately 50% of colonic carcinomas and in a similar percentage of intermediate-stage and late-stage adenomas. Allelic deletions were discovered of specific portions of chromosomes 5, 17, and 18, which presumably harbor tumor-suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is mutated, not only in colonic cancer, but also in a large percentage of other human solid tumors. The gene dcc recently was identified; this candidate tumor-suppressor gene on chromosome 18 appears to be altered in colorectal carcinomas. The protein encoded by the dcc gene has significant sequence similarity to neural cell adhesion molecules and other related cell-surface glycoproteins. By mediating cell-cell and cell-substrate interactions, this class of molecules may have important functions in mediating cell growth and differentiation. Alterations of the dcc gene may interfere with maintenance of these controls and thus may play a role in the pathogenesis of colorectal neoplasia. Another candidate tumor-suppressor gene also was identified on chromosome 5, mcc (for mutated in colorectal cancers). The mcc genetic alterations include one tumor with somatic rearrangement of one mcc allele and several tumors with somatically acquired point mutations in the coding region. Studies currently are ongoing to (1) identify additional tumor-suppressor gene candidates, (2) increase our understanding of normal tumor-suppressor gene function, and (3) demonstrate the functional tumor-suppressor ability of these genes both in vivo and in vitro.
Adenoma↗
Suppressor gene alterations in the colorectal adenoma-carcinoma sequence.
Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate to bring about the neoplastic phenotype. Colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the inactivation of several tumor suppressor genes. We have found frequent allelic deletions of specific portions of chromosomes 5, 17, and 18 which presumably harbor suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is frequently mutated not only in colon cancer but in several other tumor types as well. Candidate suppressor genes have also recently been identified on chromosomes 18 and 5. The DCC gene on chromosome 18q encodes a protein with significant sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. Alterations of this gene may interfere with normal cell growth and differentiation by disrupting cell-cell or cell-substrate interactions. Two genes (MCC and APC) on chromosome 5q have also recently been identified and partially cloned. These genes are located in a region tightly linked to familial adenomatous polyposis (FAP). While MCC mutations have been found only in sporadic colon tumors, APC mutations have been identified in sporadic tumors as well as the germline of patients with FAP. Studies are currently in progress to increase our understanding of how alterations of these genes affect colorectal tumor cell growth.
Adenoma↗
SAM 1.1 and JOSH 4.4: two RFLPs within the human DCC gene.
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Alleles↗
DCC: a tumor suppressor gene expressed on the cell surface.
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Cell Differentiation↗
Antisense RNA to the putative tumor-suppressor gene DCC transforms Rat-1 fibroblasts.
Allelic deletions involving chromosomes 18q occur in a significant number of colorectal cancers. Recently, a highly conserved gene called 'deleted in colorectal cancer' (DCC) has been identified on chromosome 18q. DCC has been postulated to be a colorectal tumor-suppressor gene. In order to understand the role of DCC in cell transformation, we have established a stable Rat-1 cell line expressing dexamethasone-inducible DCC antisense RNA. High levels of dexamethasone-inducible DCC antisense RNA were detected in the Rat-1 transfectants. The antisense DCC-expressing Rat-1 cells showed a faster growth rate, anchorage independence and tumorigenicity in nude mice. Exposure of the parental Rat-1 cells to antisense oligodeoxyribonucleotides to DCC resulted in inhibition of cell adhesion to the substratum which could be abrogated by various extracellular matrices. On the other hand, a bone marrow-derived stromal cell line which does not express DCC showed no detachment from the substratum when treated with the antisense oligo to DCC. These results suggest that the DCC gene is involved in cell adhesion and provide the first direct biological evidence for the possible role of DCC as a tumor-suppressor gene.
Animals↗
HindIII polymorphism in the DCC gene.
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Alleles↗
Evidence supporting exclusion of the DCC gene and a portion of chromosome 18q as the locus for susceptibility to hereditary nonpolyposis colorectal carcinoma in five kindreds.
Hereditary non-polyposis colorectal carcinoma (HNPCC) syndrome is characterized by early onset and multiple cancers of predominantly the proximal colon and occasionally other organs. The mode of transmission is compatible with autosomal dominant inheritance but the location and characteristics of the putative susceptibility gene are unknown. We performed linkage analyses with the aim of proving or excluding the existence of a susceptibility locus on 18q. This hypothesis was based on the frequent involvement of the DCC gene in colorectal carcinoma and on the previously reported linkage between HNPCC and the Kidd blood group locus (JK) also on 18q. Seven HNPCC families were tested with eight polymorphisms, including three from within DCC. The DCC locus could be excluded as the HNPCC susceptibility locus in five families in which the two point logarithm-of-odds scores were -3.66, -3.63, -4.12, -7.90, and -3.74 at the recombination fraction of 0.00. In the remaining two families linkage could be neither excluded nor confirmed. The added pairwise logarithm-of-odds score for all seven families was -22.65 at the recombination fraction of 0.00. Multipoint analyses of linkage in the seven families suggested exclusion of some 60 cM in the region DCC-D18S18-D18S22-D18S7 as the site for HNPCC susceptibility locus. In addition to DCC, the excluded portion comprises JK.
Adult↗
Scrambled exons.
Using a sensitive assay for RNA expression, we identified several abnormally spliced transcripts in which exons from a candidate tumor suppressor gene (DCC) were scrambled during the splicing process in vivo. Cloning and sequencing of PCR-amplified segments of the abnormally spliced transcripts showed that exons were joined accurately at consensus splice sites, but in an order different from that present in the primary transcript. Four scrambled transcripts were identified, each involving a different pair of exons. The scrambled transcripts were found at relatively low levels in a variety of normal and neoplastic cells of rodent and human origin, primarily in the nonpolyadenylated component of cytoplasmic RNA. These results demonstrate that the splicing process does not always pair sequential exons in the order predicted from their positions in genomic DNA, thus creating a novel type of RNA product.
Amino Acid Sequence↗
Dermatofibrosarcoma protuberans of the vulva.
Dermatofibrosarcoma protuberans of the vulva is an uncommon low-grade sarcoma of dermal origin. Although wide local excision is the treatment of choice, microscopic tumor projections beyond the central tumor nodule explain the tumors' propensity for local recurrence. Frozen sections of margins may be useful to ensure complete resection. The following report contributes two additional patients with this uncommon neoplasm. Notably, one of these two had a fibrosarcomatous area within the dermatofibrosarcoma protuberans. This is the second reported case of a fibrosarcoma arising in a dermatofibrosarcoma protuberans of the vulva.
Adult↗
Relationship of severe dysplasia to stage A (incidental) adenocarcinoma of the prostate.
Totally embedded radical prostatectomy specimens and their transurethral resections (TUR) from 32 Stage A (incidental) carcinomas were studied for severe dysplasia. These cases were selected to be representative of the majority of Stage A cancers and hence consisted of cases with predominantly low-grade centrally located tumor. In 43.75% of the cases, severe dysplasia was minimal in amount, 43.75% intermediate, and 12.5% extensive. Severe dysplasia was spatially associated with the main tumor in only 31.25% of cases. In 43.75% of the cases all of the severe dysplasia was isolated (i.e., not adjacent or intermingled with any carcinoma). Whereas this study confirms one general association between severe dysplasia and the presence of carcinoma within the gland, the data do not strongly support the concept that the dysplasia is a direct precursor to centrally located low-grade Stage A carcinomas. From a practical viewpoint, severe dysplasia in the TUR was seen in 15.6% of cases and was not predictive of the amount of tumor within the gland.
Adenocarcinoma↗
Relationship of severe dysplasia to stage B adenocarcinoma of the prostate.
Severe dysplasia was studied in totally embedded radical prostatectomy specimens from 40 Stage B, intermediate-grade prostate cancers. All 40 cases had severe dysplasia which varied in amount (extensive in 35% of cases; intermediate in 55%; minimal in 10%). Severe dysplasia was predominantly concentrated in peripheral and posterior regions of the gland. Those cases with extensive severe dysplasia had more multifocal small cancers (14.6/case) compared with cases with intermediate (7.5/case) or minimal severe dysplasia (5.5/case). Most dominant tumor nodules had some intermingled severe dysplasia, and in 30% of the dominant tumor nodules, intermingled severe dysplasia occupied between 10% and 25% of the tumor nodule. Severe dysplasia was located next to the dominant tumor nodule in all cases. Nineteen percent of dominant tumor nodules had extensive adjacent severe dysplasia ranging from 5 to 14 mm in maximum diameter, showing that the potential exists for needle biopsy of prostate cancers to obtain only severe dysplasia. These data show a close relationship between severe dysplasia and Stage B cancers. In contrast, centrally located low-grade multifocal cancers, as seen in Stage A (incidental) carcinoma, had a significantly weaker association with severe dysplasia as compared with central, intermediate-grade, multifocal tumors or peripheral multifocal tumors of any grade.
Adenocarcinoma↗
Identification of a chromosome 18q gene that is altered in colorectal cancers.
Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.
Alleles↗
Leiomyoma of the uterus with multiple extrauterine smooth muscle tumors: a case report suggesting multifocal origin.
A 17-year-old woman underwent hysterectomy for removal of a "mitotically active" (six to seven mitoses per 10 high-power fields) yet otherwise benign-appearing cellular smooth muscle tumor. Eleven years later, she developed multiple histologically benign smooth muscle tumors in the posterior mediastinum, deep soft tissues of the neck, paravertebral region, incisional scar, and mesentery. The distribution and histologic appearance of the tumors, as well as the protracted clinical course, suggest multifocal origin rather than widespread metastases from a low-grade uterine leiomyosarcoma. This case raises the possibility that some similar cases reported as so-called benign metastasizing leiomyoma may be more satisfactorily explained by the concept of multifocality.
Adolescent↗
Morphometric measurement of tumor volume and per cent of gland involvement as predictors of pathological stage in clinical stage B prostate cancer.
Although tumor volume is an important factor in predicting prognosis in carcinoma of the prostate, direct and accurate estimation of tumor volume is not practical clinically at present because the tumor may not always be palpable (stage A) and when palpable it is difficult to estimate volume in 3 dimensions. For this reason the clinical staging of prostate cancer currently is based on estimations of the per cent of gland involved with tumor: in stage A by per cent of tissue involved with cancer and in stage B by digital palpation (less than 1 lobe, 1 lobe and 2 lobes). In stage A prostate cancer the per cent of the specimen involved with tumor and the volume of tumor have been shown to correlate with tumor progression. Our study was designed to determine if either or both of these morphometric factors would be good predictors of pathological stage in stage B prostate cancer. We analyzed 56 step-sectioned radical prostatectomy specimens: 28 without capsular penetration, 15 with capsular penetration only and 13 with seminal vesicle involvement. The per cent of gland involved with tumor (correlation coefficient 0.67, p less than 0.001) and tumor volume (correlation coefficient 0.55, p less than 0.001) correlated well with pathological stage. Stepwise linear regression showed that the combination of the per cent of gland involved with tumor and the total Gleason grade was statistically the best predictor of pathological stage.
Adult↗
Malignant rhabdoid tumor of the uterus.
Rhabdoid tumors are highly malignant neoplasms resembling rhabdomyosarcomas, which most commonly occur in the kidney in young children. Several cases of extrarenal malignant rhabdoid tumors have been described, many in adolescents and young adults. We describe a 46-year-old woman with a primary uterine tumor that has the histologic, immunohistochemical, and ultrastructural characteristics of a malignant rhabdoid tumor. To our knowledge, this is the first report of a rhabdoid tumor in this site. Furthermore, this woman's age expands the range for which pathologists and clinicians should consider this diagnosis, even in extrarenal sites.
Female↗
Lipomeningioma: report of three cases and review of the literature.
Lipomeningioma is a benign tumor of the meninges that contains mature adipose tissue. It demonstrates fat density on computed tomographic scan and mixed signal intensities on magnetic resonance imaging scan. Although the pluripotential nature of the mesenchymal cell has long been recognized, only a single case with this diagnosis has been documented in the literature to date. Three patients with this diagnosis seen at the Johns Hopkins Hospital during the last two years are presented, and the literature is reviewed.
Aged↗
Primitive rhabdomyosarcoma presenting with diffuse bone marrow involvement: an immunohistochemical and ultrastructural study.
We recently identified three cases of primitive rhabdomyosarcoma (PRMS) presenting with diffuse bone marrow infiltration but inconspicuous soft tissue primaries, referred to The Johns Hopkins Hospital (JHH) as acute leukemia. In each case, the diagnosis of rhabdomyosarcoma was established using immunohistochemical staining and electron microscopy. Ultrastructural examination of tumor cells showed a feltwork of thin filaments, discontinuous basal lamina, glycogen, and primitive cell junctions without cell processes or neurosecretory granules. This presentation of PRMS may be more common than recognized, since it can be readily misdiagnosed as a hematopoietic tumor. While positive staining for muscle-specific actin, desmin, myoglobin, or other markers of skeletal muscle differentiation may be diagnostic, negative staining is inconclusive, requiring recognition of the "minimal" ultrastructural findings of primitive rhabdomyosarcomas.
Actins↗