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Biomedical subjects

A K Godwin

Publications and source records attributed to A K Godwin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

Adult↗
PubMed1998

Mutation detection using a novel plant endonuclease.

We have discovered a useful new reagent for mutation detection, a novel nuclease CEL I from celery. It is specific for DNA distortions and mismatches from pH 6 to 9. Incision is on the 3'-side of the mismatch site in one of the two DNA strands in a heteroduplex. CEL I-like nucleases are found in many plants. We report here that a simple method of enzyme mutation detection using CEL I can efficiently identify mutations and polymorphisms. To illustrate the efficacy of this approach, the exons of the BRCA1 gene were amplified by PCR using primers 5'-labeled with fluorescent dyes of two colors. The PCR products were annealed to form heteroduplexes and subjected to CEL I incision. In GeneScan analyses with a PE Applied Biosystems automated DNA sequencer, two independent incision events, one in each strand, produce truncated fragments of two colors that complement each other to confirm the position of the mismatch. CEL I can detect 100% of the sequence variants present, including deletions, insertions and missense alterations. Our results indicate that CEL I mutation detection is a highly sensitive method for detecting both polymorphisms and disease-causing mutations in DNA fragments as long as 1120 bp in length.

Apiaceae↗
PubMed1998

Cloning and localization of a human diphthamide biosynthesis-like protein-2 gene, DPH2L2.

Sequence analysis of the candidate tumor suppressor OVCA1 revealed extensive sequence identity and similarity to proteins from a diverse number of species, including the yeast diphthamide biosynthesis protein-2, dph2, which suggested that OVCA1 may be the human homologue to this yeast gene. However, searches of the translated EST database for sequences in common with dph2 and OVCA1 uncovered an EST, h52976, with significant amino acid conservation with dph2. Isolation of a cDNA clone encompassing the EST by RACE methodologies and sequence analysis indicate the identification of a previously unidentified gene that is ubiquitously expressed and maps to chromosome 1p34. Based on amino acid sequence analysis, the 489-amino-acid protein encoded by this novel gene is distinct from OVCA1 and is more closely related to the yeast dph2 gene product. Therefore, we refer to this novel gene as DPH2L2, which constitutes one member of a novel gene family that may be involved in diphthamide biosynthesis in humans.

Amino Acid Sequence↗
PubMed1998

Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study.

Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P=.10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P<.001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P=.0005).

Adult↗
PubMed1998

Genetics and ovarian carcinoma.

Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.

BRCA1 Protein↗
PubMed1997

The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds.

An increased incidence of colorectal cancer has been observed in breast and breast-ovarian cancer syndrome families, including those of Ashkenazi origin. Recently, a germ-line missense mutation in the APC gene, I1307K, was identified that may indirectly cause colorectal cancer in Ashkenazi Jews. To determine whether the excess of colon cancer in some breast-ovarian cancer families is related to the I1307K mutation, we evaluated 264 Ashkenazi Jews from 158 families. Most of these individuals had either a personal or a family history of breast and/or ovarian cancer, and 19.3% (51 of 264) carried one of the recurrent BRCA1 (185delAG or 5382 insC) or BRCA2 (6174delT) mutations. We detected the APC I1307K mutation in 7% (11 of 158) of the Ashkenazi Jewish families and in 4.5% (12 of 264) of the individuals participating in these studies. Of the families studied, 26.6% (42 of 158) had at least one case of colorectal cancer in a first-, second-, or third-degree relative of the proband. Significantly, of the 12 individuals who possessed the I1307K mutation, none was diagnosed with colorectal cancer and none had a known first-, second-, or third-degree relative diagnosed with colon cancer. The results suggest that factors other than the I1307K mutation contribute to the increased incidence of colon cancer in Ashkenazi breast-ovarian cancer families. Our results emphasize that only a subset of Ashkenazi Jewish individuals with a family history of colorectal cancer should be viewed as candidates for genetic susceptibility testing for the I1307K APC mutation.

Aged↗
PubMed1997

Molecular cloning and characterization of LOH11CR2A, a new gene within a refined minimal region of LOH at 11q23.

Deletions at chromosome 11q23 are frequent events in a variety of human neoplasms, including breast, lung, and ovarian carcinomas. Two common regions of loss of heterozygosity, shared between lung and breast carcinomas, have been previously identified at 11q23, suggesting that the same tumor susceptibility genes are altered in these two malignancies. One of these regions, refined in lung adenocarcinoma, is included between loci D11S1345 and D11S1328. Here, we describe the refinement of the same region in breast carcinomas and the characterization of a new gene found within this area. The gene, called LOH11CR2A, spans an area of approximately 40 kb and is transcribed at a low level in all the tissues in which it has been analyzed. The predicted amino acid primary sequence revealed no homology with other proteins that could help to elucidate a possible function for the LOH11CR2A protein. Here, we tested the hypothesis that LOH11CR2A could be a tumor suppressor gene. Analysis of human breast, lung, and ovarian carcinomas revealed the presence of several amino acid substitutions in the coding region of this gene. However, a role for these amino acid changes in the tumorigenic process could not established.

Amino Acid Sequence↗
PubMed1997

Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells.

We have used a rat model of epithelial ovarian cancer to identify a gene that shows decreased or lost expression in five of eight independently transformed rat ovarian surface epithelial cell lines compared to the normal progenitor cells. Hence, we refer to this gene as Lot1 (lost on transformation 1; GenBank accession no. U72620). The most abundant transcript of the gene is approximately 6 kb. This sequence contains a 1749-nucleotide open reading frame and, within the 3' untranslated region, 22 near-perfect 60-70-bp repeats and adenine- and uracil-rich areas. The deduced amino acid sequence from the open reading frame contains seven zinc-finger motifs of the C2H2 type, as well as proline-, glutamine-, and glutamic acid-rich areas. The gene maps to the short arm of chromosome one in the rat. Lot1 shows a limited distribution of expression in normal rat tissues, including ovary, which shows abundant expression. Furthermore, examination of DNA derived from multiple species indicates that the gene is widely conserved.

Amino Acid Sequence↗
PubMed1997

Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors.

We have used a rat model of epithelial ovarian cancer to identify a gene that shows decreased or lost expression in independently transformed rat ovarian surface epithelial cell lines compared to the normal progenitor cells. Hence, we refer to this gene as Lot-1 (Lost on transformation 1, GenBank accession no. U72620). Here, we report the cloning of the likely human homologue and its initial characterization. The deduced amino acid sequences of the cDNAs for rat and human LOT-1 (GenBank accession no. U72621) contain seven zinc finger motifs of the C2H2 type as well as proline and glutamine rich areas. The genes share 76.4% identity at the nucleotide level, 67.7% at the amino acid level and 85.5% within the seven zinc finger motifs. LOT-1 is ubiquitously expressed in normal human tissues but was not expressed in four of 11 (36%) human ovarian cancer cell lines or spontaneously transformed human ovarian surface epithelial cells. The human gene maps to chromosome 6 at band q25. We show that there is a 38% incidence of allelic loss at this chromosomal location in human ovarian cancers. This chromosomal region has also been implicated in the genesis of breast, kidney, and pleural mesothelial cancers. We suggest that this newly identified gene is not only of intrinsic interest as a ubiquitously expressed probable transcription factor but is a plausible candidate for the tumor suppressor gene which likely resides in the region of chromosome 6 defined by band q25.

Amino Acid Sequence↗
PubMed1997

Detection of DNA gains and losses in primary endometrial carcinomas by comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used in a retrospective analysis of chromosomal imbalances in frozen primary tumor specimens from 14 endometrial carcinoma patients. Chromosome changes were detected in nine cases (64%), and tumor stage and grade tended to parallel the degree of genomic imbalances. Gain of the entire long arm of chromosome 1 was observed in six cases (43%), three of which displayed only this chromosome change. Other common sites of copy number increases included 8q21-->qter (4 cases), 10p15 (4 cases), 10q11-->q24 (3 cases), and 13q21-->qter (3 cases, each with stage III disease). Two of the tumors with gains of chromosome 10 involved the whole chromosome, and this was the sole abnormality in one case. DNA amplification at 5p14-->p15 was identified in one specimen, a stage III tumor having numerous imbalances. DNA microsatellite analysis revealed multiple replication errors (RER), indicative of the RER+ phenotype, in four of 13 (31%) cases evaluated. The RER+ phenotype was observed in four of six stage la tumors but in none of seven stage Ib or stage III tumors. Multiple genomic imbalances detected by CGH were not observed in RER+ tumors but were detected in five of nine tumors without the RER+ phenotype. These investigations demonstrate the feasibility of CGH for the retrospective assessment of chromosomal changes in endometrial carcinoma specimens. Moreover, these data suggest that the etiologies in tumors with and without the RER+ phenotype may differ.

Aged↗
PubMed1997

Defining etiologic heterogeneity in breast cancer using genetic biomarkers.

Most breast cancer has a complex, multifactorial etiology. One consequence of this multifactorial phenomenon is that etiological heterogeneity may exist. This heterogeneity implies simply that two or more groups of breast cancer cases in the general population may have been caused by different sets of events. The ability to define etiologically heterogeneous subgroups in the population may facilitate a number of research and clinical issues. Studying etiologically homogeneous subgroups in the general population may improve the ability to identify etiologic agents. Identification of a homogeneous group of breast cancer cases may also aid breast cancer diagnosis or treatment, and may allow a more effectively application of cancer prevention and control strategies. Defining etiologic heterogeneity in the general population is one initial step in the process of understanding cancer etiology. Using knowledge such as that provided in the two examples presented here, formal case-control or cohort studies can be undertaken to examine whether the factors that define etiologic heterogeneity are involved in etiology. Furthermore, the results of studies of etiologic heterogeneity can point toward potential gene-gene or gene-environment interactions. The type of studies presented here can therefore serve a useful role in leading to more formal molecular epidemiological analyses.

Age of Onset↗
PubMed1997

Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas.

We used comparative genomic hybridization (CGH) to identify recurrent chromosomal imbalances in tumor DNA from 25 malignant ovarian carcinomas and two ovarian tumors of low malignant potential (LMP). Many of the carcinoma specimens displayed numerous imbalances. The most common sites of copy number increases, in order of frequency, were 8q24.1, 20q13.2-qter, 3q26.3-qter, 1q32, 20p, 9p21-pter, and 12p. DNA amplification was identified in 12 carcinomas (48%). The most frequent sites of amplification were 8q24.1-24.2, 3q26.3, and 20q13.2-qter. Other recurrent sites of amplification included 7q36, 17q25, and 19q13.1-13.2. The most frequent sites of copy number decreases were 5q21, 9q, 17p, 17q12-21, 4q26-31, 16q, and 22q. Underrepresentation of 17p was observed in six of 16 stage III/IV tumors, but in none of seven stage I/II tumors, suggesting that this change may be a late event associated with the transition of ovarian carcinomas to a more metastatic disease. Overrepresentation of 3q26.3-qter, 5p14-pter, 8q24.1, 9p21-pter, 20p, and 20q13.2-qter and underrepresentation of 4q26-31 and 17q12-21 also tended to be more common in advanced-stage tumors. All ten grade 3 tumors had copy number increases involving 8q24.1, compared to only three of nine grade 2 tumors. Overrepresentation of 3q26.3-qter and 20q13.2-qter was also observed at a higher frequency in high-grade tumors. One of the two LMP tumors displayed chromosomal alterations, which consisted of overrepresentation of 5p and 9p only. Taken collectively, these findings and data from other CGH studies of ovarian cancers define a set of small chromosome segments that are consistently over- or underrepresented and, thus, highlight sites of putative oncogenes and tumor suppressor genes that contribute to the pathogenesis of these highly malignant neoplasms.

Adult↗
PubMed1996

Autonomy of the epithelial phenotype in human ovarian surface epithelium: changes with neoplastic progression and with a family history of ovarian cancer.

Epithelial ovarian carcinomas originate in the ovarian surface epithelium (OSE). In culture, OSE undergoes epithelio-mesenchymal conversion, an event mimicking a wound response, while ovarian carcinomas retain complex epithelial characteristics. To define the onset of this increased epithelial autonomy in ovarian neoplastic progression, we examined mesenchymal conversion in OSE from 25 women with no family histories (NFH-OSE) and 13 women with family histories (FH-OSE) of breast/ovarian cancer (including 8 with mutated BRCA1 or 17q linkage) and in 8 ovarian cancer lines. After 3-6 passages in monolayer culture, most NFH-OSE exhibited reduced keratin expression and high collagen type III expression. In contrast, keratin remained high but collagen expression was lower in p. 3-6 FH-OSE. This difference was lost in SV40-transformed lines, which all resembled FH-OSE. Most carcinoma lines remained epithelial and did not undergo mesenchymal conversion. In 3-dimensional (3-D) sponge culture, NFH-OSE cells dispersed and secreted abundant extracellular matrix (ECM). FH-OSE remained epithelial and did not secrete ECM. ECM production was also reduced in SV40-transformed lines. Carcinoma lines in 3-D formed epithelial cysts, aggregates and papillae and lacked ECM. Sponge contraction (a mesenchymal characteristic) was greater in NFH-OSE than in FH-OSE both before and after SV40 transformation and was absent in the cancer lines. Our results suggest that increased autonomy of epithelial characteristics is an early indicator of ovarian neoplastic progression and that phenotypic changes indicative of such autonomy are found already in overtly normal OSE from women with histories of familial breast/ovarian cancer.

Biomarkers, Tumor↗
PubMed1996

Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies.

BACKGROUND: The occurrence of approximately 5% of common epithelial malignant tumors of the ovary can be traced to inheritance of risk. One prophylactic strategy to decrease the probability of development of disease in individuals within families where this mendelian-dominant pattern of occurrence is apparent is to remove the ovaries of individuals at risk for ovarian cancer. The procedure, when done for this purpose, is recommended soon after completion of childbearing. PURPOSE: Our goal was to compare the histologic features of the ovaries of women at increased risk for ovarian cancer to those at no known increased risk for the disease. METHODS: Ovaries removed for prophylaxis from 20 women considered to be at increased risk for developing ovarian cancer were examined histologically. During the course of this work, it seemed apparent that these ovaries contained numerous atypical features compared with the expected appearance of normal ovaries. Hence, we expanded the study to include a control group whose ovaries were removed for reasons unrelated to cancer. The study, therefore, was not blinded. The increased risk in the cancer-prone individuals was determined by family history, specifically the presence of at least one first-degree relative and one second-degree relative with ovarian and/or breast cancer and positive linkage or mutational analysis of BRCA1 in some. The difference in mean ages of patients in the control and high-risk groups was not statistically significant. The difference among both groups with respect to the number of atypical features as well as the intensity of those features was ascertained by computing probabilities using Fisher's exact test (two-sided) for rows x columns contingency tables. RESULTS: Two unanticipated microscopic or near-microscopic malignant neoplasms and other benign and borderline tumors were discovered in the ovaries of the high-risk individuals. Of substantial interest was the finding that among the ovaries of high-risk women, 85% presented two or more and 75% presented three or more of the following histologic features: surface epithelial pseudostratification; surface papillomatosis; deep cortical invaginations of the surface epithelium, frequently with multiple papillary projections within small cystic spaces (microscopic papillary cystadenomas); epithelial inclusion cysts, frequently with epithelial hyperplasia and papillary formations; cortical stromal hyperplasia and hyperthecosis; increased follicular activity; corpus luteum hyperplasia; or hilar cell hyperplasia. Two or more or three or more such changes were observed in a lesser percentage (30% or 10%, respectively) of ovaries obtained from the control individuals, with a statistically significant difference (P = .001 or P = .00007, respectively), particularly considering that a detailed determination of a family history of cancer in the control group was not possible. CONCLUSIONS: The frequency of these changes in the high-risk ovaries compared with control ovaries suggests a characteristic histologic preneoplastic phenotype defined by an increased frequency and intensity of the above-described histologic features in the high-risk ovaries. Limited access to numerous small (stage I) ovarian cancers or cancer-prone ovaries by any one pathologist may explain the failure to identify the phenotype in the past. IMPLICATIONS: We suggest that the ovaries removed from ovarian cancer-prone individuals as a preventative measure should be thoroughly examined histologically to identify or rule out microscopic or near-microscopic invasive neoplasms.

Adult↗
PubMed1996

A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.

Recent studies have identified mutations in the breast and (ovarian cancer susceptibility gene 2 (BRCA2), one which has been found in the germline of several males and one female affected with breast cancer. To establish the carrier frequency of this mutation in a large population of individuals affected with cancer, we evaluated constitutional DNA isolated from 83 individuals diagnosed with breast cancer and 93 diagnosed with ovarian cancer at any age, 42 of whom reported a family history of cancer. Using a simple allele-specific PCR-based nonradioactive method, we detected a total of eight individuals (4.5%) carrying a 1-bp deletion at nucleotide 6174 of the BRCA2 gene (6174delT). The age of disease onset in the mutant allele carriers was highly variable and typically late onset (41-72 years for breast cancer and 48-73 years for ovarian cancer). Evaluation of family histories for the eight mutant allele carriers revealed that several individuals had significant cancer histories that included, in addition to breast and/or ovarian cancer, an increased incidence of colon, esophageal, pancreatic, stomach, and hematopoietic cancers. Interestingly, seven of the eight individuals were of Ashkenazi Jewish descent. Haplotype data for the mutant allele carriers using markers spanning the region of the BRCA2 gene on chromosome 13ql2-ql3 suggest that only two of the confirmed Jewish Ashkenazi individuals share a single common ancestry, indicating several independent origins for this mutation. These data provide evidence for the presence of a specific BRCA2 mutation which has its origins in both Jewish Ashkenazi and non-Jewish populations. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually help contribute to the development of inexpensive and routine tests such as the one described in our study.

Adult↗
PubMed1996

Increased DT-diaphorase expression and cross-resistance to mitomycin C in a series of cisplatin-resistant human ovarian cancer cell lines.

In a series of ovarian carcinoma cell lines selected in vitro for resistance to cisplatin by continuous exposure to increasing drug concentrations, the level of resistance is proportional to the expression of gamma-glutamylcysteine synthetase (gamma-GCS). To determine if other detoxicating genes are coordinately expressed, we measured the activity of DT-diaphorase and cytochrome P450 reductase. The specific activity of DT-diaphorase, but not that of cytochrome P450 reductase, increased with increasing resistance to cisplatin. Steady-state mRNA levels for DT-diaphorase correlated with enzyme activity and hence with cisplatin resistance. Since the activity of DT-diaphorase has been associated with sensitivity to quinones, we studied the cytotoxicity of mitomycin C under oxic conditions. Unexpectedly, resistance to mitomycin C increased proportionally with that to cisplatin (r = 0.997). Pretreatment with buthionine sulfoximine, which inhibits glutathione (GSH) synthesis, failed to sensitize either the sensitive or the resistant lines to mitomycin C. Thus, the basis for collateral resistance to mitomycin C in the cisplatin-resistant lines under oxic conditions is unrelated to overproduction of GSH. Under hypoxia, the toxicity of mitomycin C to the most sensitive (A2780) cell line was unchanged. However, the most resistant (C200) line was 2-fold more resistant to mitomycin C under hypoxic conditions. The coordinate overexpression of DT-diaphorase and gamma-GCS in the resistant cell lines is thus associated with hypoxic cell resistance, and supports the involvement of shared mechanisms of gene regulation in the observed resistant phenotype.

Antineoplastic Agents↗
PubMed1996

Identification of two candidate tumor suppressor genes on chromosome 17p13.3.

A second tumor suppressor locus on 17p that is distinct from TP53 has been identified in brain, breast, lung, and ovarian tumors. Using allelic loss mapping and positional cloning methods, we have recently identified two novel genes, which we refer to as OVCA1 and OVCA2, that map to 17p13.3. The two genes are ubiquitously expressed and encode proteins of 443 and 227 amino acids, respectively, with no known functional motifs. Sequence comparison of OVCA1 and OVCA2 revealed extensive sequence identity and similarity to hypothetical proteins from Saccharomyces cerevisiae, Caenorhabditis elegans, and Rattus species. Northern blot analysis reveals that OVCA1 and OVCA2 mRNA were expressed in normal surface epithelial cells of the ovary, but the level of this transcript is significantly reduced or is undetectable in 92% (11/12) of the ovarian tumors and tumor cell lines analyzed. The location, high degree of amino acid conservation, and reduced expression in ovarian tumors and tumor cell lines suggest that decreased expression of these two genes contributes to ovarian tumorigenesis and should be considered candidate tumor suppressor genes.

Alleles↗