Frequent allelic imbalance of tumor suppressor gene loci in cervical dysplasia.

In addition to human papillomavirus (HPV) infection, loss of heterozygosity (LOH) at tumor suppressor gene loci has been frequently observed in cervical cancer. Thus, it may be assumed that detection and characterization of specific LOH profiles in preneoplastic lesions, in addition to HPV typing, might facilitate assessment of progression risk of cervical dysplasia. In this study, the type and frequency of allelic imbalance (allelic loss or allelic reduction) were analyzed in 24 unrelated cervical lesions using 14 polymorphic microsatellite markers at different tumor suppressor gene loci. No allelic loss was observed in four condylomatous lesions, whereas 2 of 13 (15%) CIN I lesions displayed allelic loss at 3p25 and 5q11-13. In high-grade lesions, however, allelic loss occurred in four of six (66%) cases at multiple chromosomal regions (3p14-25, 5p15, 5q11, 5q21, 11p15, and 17q21). Allelic reduction was observed in 4 of 13 (30%) low-grade lesions and 3 of 6 (50%) high-grade lesions. LOH was confined to lesions infected by high-risk HPV types. These data suggest that chromosomal instability is an early event in cervical carcinogenesis. The detection of LOH on multiple chromosome 3p loci in 50% of high-grade lesions suggests that a specific marker panel encompassing this region might enable better assessment of which lesions are likely to regress, persist, or progress.     

Allelic deletion mapping on chromosome 6q and X chromosome inactivation clonality patterns in cervical intraepithelial neoplasia and invasive carcinoma

OBJECTIVE: Loss of heterozygosity (LOH) profiles and X chromosome inactivation patterns are analyzed in 42 patients with cervical intraepithelial neoplasias (CIN), including low-grade (CIN1) and high-grade (CIN2, CIN3) lesions, and 22 patients with invasive cervical carcinomas. METHOD: Laser capture microdissection was utilized to procure pure matched normal and lesional cells from each case. Sixteen microsatellite markers on four chromosomal arms, 6q21-q25.1, 8p21, 13q12.3--q13, and 17q12--q21, were amplified for LOH, as well as the HUMARA locus for X chromosome inactivation analysis. Eight additional markers spanning the long arm of chromosome 6 were utilized in all cases showing LOH on this arm and in which further tissue material was available for microdissection. RESULTS: Fifty-five percent of carcinomas showed deletions on chromosome bands 6q21--q25.1, 43% on 13q12.3--q13, and 40% on 17q12--q21. Deletions on 6q were identified in CIN3 (40%), CIN2 (37%), and CIN1 (10%), on 13q in CIN3 (33%) and CIN2 (33%), and rarely on chromosomal arm 17q. Finer 6q mapping revealed that marker D6S310 (q22) represented the centromeric and marker D6S255 (q25--q16) the telomeric boundary of deletion. A second, telomeric area of deletion at marker D6S281 (q27) was also identified. Monoclonal X chromosome inactivation patterns were identified in 12/13 cancers, 13/14 CIN3, 5/10 CIN2, and 0/6 CIN1. CONCLUSIONS: Two areas of deletion on chromosome 6q were identified in cervical tumors, suggesting the presence of tumor suppressor gene(s) inactivated in this neoplasia. LOH on this arm were identified early during cervical tumor progression. LOH on 13q and 17q also occur in cervical cancers. X chromosome inactivation patterns suggest that CIN develops into a monoclonal lesion during progression from CIN1 to CIN3.     

Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants

OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.     

Utility of the monoclonal antibody HIK1083 in the diagnosis of adenoma malignum of the uterine cervix

OBJECTIVES: The aim of this study was to qualify a staining technique for the diagnosis of adenoma malignum. METHODS: The gastric mucin expression of adenoma malignum, ordinary endocervical adenocarcinoma, and normal cervical glands was immunohistochemically compared using the monoclonal antibody HIK1083. RESULTS: The three categories were clearly distinguished, with 90% (9/10) of cases with positive adenoma malignum, 30% (3/10) of cases with weakly positive ordinary cervical adenocarcinoma, and no (0/10) cases of positive normal cervical glands. CONCLUSIONS: This preliminary report indicates that the use of HIK1083 is valuable in the diagnosis of adenoma malignum.     

Allelotype of papillary serous peritoneal carcinomas.

OBJECTIVE: Papillary serous peritoneal carcinoma (PSPC) is histologically indistinguishable from papillary serous ovarian carcinoma (PSOC) with a similar clinical presentation, yet may differ in its carcinogenesis. The purpose of this study was to determine the incidence of allelic loss and the frequency of p53 mutation by p53 overexpression in PSPC compared to PSOC. METHODS: An allelotype analysis of 26 patients with PSPC was performed using 39 microsatellite markers from 25 chromosomal arms. Thirty-seven previously studied patients with PSOC served as the comparison. P53 mutations were detected by immunohistochemical protein overexpression. RESULTS: There was significantly less LOH in PSPC than PSOC. Both the number of chromosomes with LOH and the proportion of tumors with allelic loss were less frequent. Significant LOH, defined as >/=30% of informative tumors having loss at a chromosome locus, was seen on 4 chromosome arms in PSPC: 12p, 17p, 17q, and 18q, compared to 18 arms in PSOC: 4q, 5q, 6p, 6q, 9p, 9q, 12p, 12q, 13q, 15q, 16q, 17p, 17q, 18q, 19p, 19q, 22q, and Xq (P < 0.001). The median LOH frequency was higher in PSOC than PSPC, 43% versus 33%, respectively (P = 0.013), and more PSOC tumors had LOH than PSPC tumors, 91% versus 65% (P = 0.042). P53 overexpression was detected in 80% of PSPC tumors. CONCLUSIONS: LOH occurs less frequently in PSPC compared to PSOC. Chromosomal regions with high frequencies of LOH common to PSPC and PSOC, such as 12p, 17p, 17q, and 18q, may harbor tumor suppressor genes important in the carcinogenesis of both malignancies and likely include p53.     

Microsatellite instability is a late event in the carcinogenesis of uterine cervical cancer

OBJECTIVE: The purpose of this study was to elucidate the role of genetic instability and LOH in the progression of cervical cancer and also to analyze for correlations between these genetic abnormalities and the clinicopathological characteristics of cervical cancers. METHODS: Seventy-two DNA samples were obtained from 29 carcinoma in situ, 8 microinvasive carcinoma, and 35 invasive cancers. Seven highly polymorphic microsatellite markers representing the chromosome 3p, 6p, and 6q arms were examined by PCR amplification. RESULTS: Microsatellite instability was detected in 8 of 35 (22.9%) invasive cancers and in 1 of 37 (2.7%) early stage cancers (microinvasive cancer and carcinoma in situ). The incidence of MI was statistically higher in invasive cancers (P < 0.02). On the other hand, loss of heterozygosity (LOH) of chromosome 3p was identified in 6/41 (14.6%) invasive cancers and in 3/27 (11.1%) carcinomas in situ. There was no statistical difference between the two groups. There were no significant correlations between the presence of MI or 3p LOH and clinicopathological characteristics including the histological type, FIGO stage, depth of myometrial invasion, lymphovascular involvement, lymph node metastasis, and recurrence. CONCLUSION: Our results indicate that genomic instability is a late event during the carcinogenesis of cervical cancer and is associated with the conversion of cervical intraepithelial neoplasia to an invasive phenotype. To the contrary, LOH of chromosome 3p plays an early role in the development of cervical intraepithelial neoplasia. No significant correlation was observed between the presence of MI or LOH and clinicopathological characteristics.     

X chromosomal and autosomal loss of heterozygosity and microsatellite instability in human cervical carcinoma

The study analyzes tumor material and normal tissue from 27 patients with pure squamous cell carcinoma of the uterine cervix for loss of heterozygosity (LOH) and microsatellite instability (MSI) on 14 autosomal and 11 X chromosomal loci. Overall, 4-40% of the informative cases showed LOH at autosomal regions with the highest frequency at 3p (21-40%) and a marked frequency at 2q35-q37.1 (12.5%) and 17p13.3 (10%), representing regions with putative tumor suppressor gene (TSG) function. The frequency of X chromosomal LOH ranged from 4% to 20%, with a maximum at Xq28 (20%) and Xq11.2-q12 (17%), again indicating alterations in TSG. A 12% LOH was seen at Xq21.33-q22.3, a region encoding a protein with a regulatory function in the cell cycle via cyclin-dependent kinases. MSI was detected in autosomal regions in up to 7% in regions linked to the X chromosome in up to 11%, probably indicating alterations of mismatch repair mechanisms. Our results and those obtained from the literature suggest that autosomal LOH and MSI in carcinomas of the cervix uteri are predominantly found at regions with putative TSG function. Beside TSG alterations, X chromosomal LOH is probably more strongly connected to disturbances in cell cycle regulation.     

Investigation of loss of heterozygosity at specific loci on chromosomes 3p, 6q, 11p, 17p and 17q in ovarian cancer

In an attempt to further define the genetic events in the pathogenesis and progression of human ovarian cancer, an analysis of constitutional and ovarian carcinoma DNA samples revealed loss of heterozygosity (LOH) at specific loci on chromosomes 3p (38%), 6q (23%), 11p (33%), 17p (82%) and 17q (62%). In contrast, LOH was not observed in benign or borderline tumors. No significant association could be demonstrated between LOH at the loci studied and tumor stage, histologic subtype, grade or patient outcome. Further analyses of large tumor panels are now required to determine the relationship between LOH at these loci and the clinicopathological behavior of ovarian tumors.     

LOH of chromosome 6q compared with LOH of 17q and 18q in ovarian cancers: relationship to p53 expression and clinicopathological findings

In 41 ovarian epithelial tumors (7 borderline and 34 invasive), loss of heterozygosity (LOH) of chromosomes 6q, 17q, and 18q was examined using 4 microsatellite markers: ER (6q 25–1), BRCA1 (17q21), DCC (18q21), and D18S58 (18q23). The LOH was compared with clinicopathological findings, including p53 and ER expression. In borderline tumors, LOH and p53 expression were never found, while in invasive carcinomas LOH and p53 were found in 71% and 59% of cases, respectively. In particular, in invasive carcinomas 6q LOH represented a marker distinguishing two groups of tumors; those with 6q LOH were only of serous histotype and at advanced stages (III/IV). No significant difference was found for any of genes in 5-year survival of the patients. No correlation was found between ER expression and ER LOH, as well as between biological aggressiveness and 17q and/or 18q LOH.
We conclude that p53 and LOH of the investigated loci distinguish borderline from invasive ovarian carcinomas; moreover, the comparison of these results with clinicopathological parameters suggests that the presence of 6q LOH may be a factor accounting for greater biologic aggressiveness independent of the histologic subtype.     

Loss of heterozygosity alterations associated with progesterone therapy in endometrial hyperplasia and adenocarcinoma

Loss of heterozygosity (LOH) was analyzed in four patients with endometrial hyperplasia (EH) with atypia (two patients) and without atypia (two patients) and in five patients with endometrial adenocarcinoma (EAC) to clarify the clinicopathologic relationship between genetic alterations and hormone therapy. Each patient was initially administered high-dose medroxyprogesterone acetate (MPA) as a uterine-sparing treatment. The five microsatellite markers used to analyze LOH were at chromosomal loci 8p22.1, 8p21, 8p21.3, 8p22, and 8p22. DNA was extracted from paraffin-embedded sections before, during, and after MPA therapy using laser capture microdissection. As a result, LOH was more frequently detected after MPA therapy (overall ratios were 16, 17, and 29% before, during, and after MPA therapy, respectively). LOH is more easily detected in EH loci than in EAC loci before MPA. For EAC, initial LOH detection on chromosome 8 may be related to an incomplete response to MPA, but negative LOH does not guarantee a favorable treatment outcome. For EH or atypical endometrial hyperplasia, it is unknown whether LOH alteration associated with MPA therapy is related to atypia of the disease.     

Molecular genetic changes in human epithelial ovarian malignancies.

The frequent finding of loss of heterozygosity (LOH) for a specific chromosomal marker in tumor DNA compared to normal DNA suggests the presence of a closely linked tumor-suppressor gene. Using Southern blot analysis, 34 primary ovarian epithelial tumors were examined for the presence of tumor-specific allelic losses, using six probes for chromosomes 6q, 11p, 13q, 16q, and 17p. A high incidence of LOH was observed on 11p, 13q, and 17p. LOH for 17p was present in 3 of 4 (75%) informative benign ovarian tumors, 1 of 5 (20%) borderline tumors, and 16 of 24 (67%) invasive ovarian cancers. Allelic loss with the H-ras1 probe on 11p was present in 10 of 19 (53%) invasive tumors but was not identified in 6 benign or borderline tumors. LOH on 13q was present in 18 of 31 (58%) informative cases including 8 of 10 (80%) Stage 1 tumors. This preliminary study suggests that loss of tumor-suppressor genes on chromosomes 13q and 17p may be early events in ovarian tumorigenesis and that changes on chromosome 11p are later events.     

Detecting and investigating the significance of high-frequency LOH chromosome regions for endometriosis-related candidate genes

To detect the high-frequency loss of heterozygosity (LOH) chromosome regions for ectopic endometrium of ovarian endometriosis (EMs) and to investigate the significance of high-frequency LOH chromosome regions in EMs, we obtained ectopic endometrium by laser capture microdissection (LCM (22 samples)), manual capture microdissection (MCM (18 samples)), and routine dissection (14 samples), respectively. After restriction and circularization-aided rolling circle amplification (RCA-RCA), LOH was detected at 12 microsatellite (MS) loci. The frequency of LOH was 59.09% (13/22) in LCM group, 61.11% (11/18) in the MCM group and 21.43% (3/14) in the routine dissection group. The latter was significantly lower when compared with the former two (p < 0.05). In the LCM group, candidate chromosome regions 17q21.31 and 9p21.3 had LOH frequencies of 23.8 and 13.6%, respectively. The highest LOH frequency was detected at the locus AAAT2 on chromosome 17q21.31 (40%). The chromosome region with the highest frequency of LOH for ectopic endometrium was 17q21.31, especially at the AAAT2 locus, which prompted that down regulation of the candidate genes nearby the locus might be one of the mechanisms of EMs pathogenesis. LCM combined with RCA-RCA is a reliable technique for analyzing endometrial LOH at multiple MS loci. MCM combined with RCA-RCA, which provided similar results, was more cost-effective.     

Clinicopathologic significance of loss of heterozygosity on chromosome 1 in cervical cancer

OBJECTIVES: We studied the loss of heterozygosity (LOH) in chromosome 1 in squamous cell carcinoma (SCC) of the uterine cervix and evaluated its clinical and pathological significance. METHODS: Sixty-three highly polymorphic markers were used to study the LOH in 84 SCC. Microdissection was performed to enrich the tumor cells population before the alleotyping study. The findings were correlated with clinicopathologic findings. RESULTS: LOH was detected in all but one SCC. The number of loci showing LOH in each case ranged from 0 to 41. Five loci showed LOH in > or =30% SCC and 28 other loci had an LOH frequency between 20% and 30%. Six of the eight markers located at 1p36.21 to 1p36.33 had a frequency of LOH >20%. Shortened total survival was associated with LOH at 14 loci and shortened disease-free survival was associated with LOH at 11 loci while LOH at nine loci were associated with both. A high frequency of LOH was associated with stage as well as shortened total and disease-free survival. CONCLUSIONS: LOH is a common and early event in the development of cervical SCC. Tumor suppressor genes may be present at 1p36. The incidence of LOH increases as the tumor progresses but a high frequency of LOH is not an independent prognostic factor.     

Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin.

Five cases of cervical squamous cell carcinoma with synchronous superficial squamous cell carcinoma in the upper genital tract were genetically analyzed to demonstrate the possibility of a clonal neoplastic process. In these cases, the cervical lesions were squamous cell carcinoma in situ (cases 1, 2, and 3) and invasive squamous cell carcinoma (cases 4 and 5). Loss of heterozygosity (LOH) analyses with a panel of microsatellite markers revealed a monoclonal process in four of the five cases. Homogeneous LOH throughout the microdissected lesions was most frequently detected on 6p and 6q (3 cases), followed by 11p and 11q (2 cases), loci known to be commonly lost in typical cervical squamous cell carcinoma. In two cases, genetic progression in terms of additional LOH was found in the upper genital tract but not in the cervix. Most of these squamous cell carcinomas were monoclonal neoplasms originating from the cervical mucosa with subsequent superficial migration of the tumor clone to the upper genital mucosa, and in some cases, genetic progression.     

Comparison of the genetic alterations in two epithelial collision tumors of the uterine cervix. A report of two cases.

In a minority of cervical carcinomas, a distinct adenocarcinoma and squamous cell carcinoma component can be recognized. These tumors are considered collision tumors; the differential diagnosis is adenosquamous carcinoma. To investigate whether the squamous and adenocarcinoma component are of multiclonal or monoclonal origin, we used loss of heterozygosity (LOH) as a method to establish clonality. Each tumor component of two tumors with a distinct adenocarcinoma and squamous cell carcinoma component were microdissected and the presence of LOH was studied for nine chromosomes, i.e., 1, 2, 3, 6, 11, 15, 17, 18, and X, which are known to contain frequent LOH in cervical cancer. The tumor of patient AK13 showed identical LOH in both the adenocarcinoma and squamous cell carcinoma tissue with various microsatellite markers on chromosomes 1, 2, 6, 18, and X. For markers on chromosomes 3 and 15, different LOH patterns were found in both components. The squamous epithelium showed LOH on chromosome 3, whereas the adenocarcinoma component had LOH on chromosome 15. For patient AK18 the LOH pattern on chromosomes 6p and 17 was the same in the adenocarcinoma and the squamous cell carcinoma component. The adenocarcinoma component showed additional LOH on chromosomes 6q and chromosome 11q. The tumor of patient AK18 showed common boundaries of LOH in both components on chromosome 17q, between markers D17S578 and D17S250. In conclusion, the squamous cell carcinoma and adenocarcinoma components in both tumors most likely have one cell of origin because many genetic alterations are the same in each component. The presence of genetic changes uniquely associated with one of the tumors favors a diversion of developmental pathways.     

Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas.

OBJECTIVE: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. METHODS: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. RESULTS: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). CONCLUSION: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers.     

Profile of chromosomal aberrations in different gestational age spontaneous abortions detected by comparative genomic hybridization

OBJECTIVE: To determine the frequency and type of chromosomal aberrations in different gestational age spontaneous abortions. STUDY DESIGN: In the study, 106 spontaneous abortions (SAs) were studied by comparative genomic hybridization. RESULTS: The frequency of detected chromosomal aberrations was 37.7%. Numerical chromosomal aberrations were disclosed in 82.5% of the aberrant cases, while structural chromosomal aberrations-in 17.5%. Highest frequency of aberrations was detected in the blighted ovum specimens (62.5%) compared to missed and second trimester SAs (respectively, 36.0% and 34.8%). With regard to structural aberrations, the difference in the frequencies between blighted ovum specimens and second trimester SAs nearly reached statistical significance (p=0.0847). However, due to the low number of blighted ovum specimens analyzed (n=8), this result should be interpreted with due caution. The most frequently affected chromosomal arms were Xp and Xq (13.7% of aberrant chromosomal arms, each), followed by 16p (8.4%), 16q (8.4%), 15q (4.2%) and 19q (4.2%). CONCLUSIONS: We describe for the first time a profile of chromosomal aberrations in SAs from different gestational ages, detected by CGH. Our results showed highest frequency of chromosome aberrations in blighted ovum specimens compared to other types of spontaneous abortions, higher rate of structural aberrations than reported before (17.5%) and some aberrations that so far were not found by CGH.     

Peutz-Jeghers syndrome with “adenoma malignum” of the cervix: A report of two cases

Two cases of the Peutz-Jeghers syndrome associated with cervical adenocarcinoma of the “adenoma malignum” type are reported with a review of four similar cases, three of which have been reported elsewhere. One of our two patients also had bilateral ovarian sex cord tumors with annular tubules and the other had bilateral ovarian mucinous cystadenomas of borderline malignancy. The relatively frequent occurrence of “adenoma malignum” of the cervix, an otherwise rare form of cervical cancer, in women with the Peutz-Jeghers syndrome, warrants close supervision of these patients by a gynecologist to assure early detection and treatment of this highly malignant tumor.     

Evaluation of a region on chromosome 1p in ovarian serous carcinoma that is frequently deleted in uterine papillary serous carcinoma.

OBJECTIVE: The goal of this study was to assess the involvement of chromosome 1p deletion in ovarian papillary serous carcinoma (OPSC) via high-resolution physical mapping to detect a candidate tumor suppressor gene previously implicated in uterine papillary serous carcinoma (UPSC) tumorigenesis. METHODS: Previous studies have demonstrated a high rate of loss of heterozygosity (LOH) within a critical region of chromosome 1p in UPSC, suggesting the presence of a putative tumor suppressor gene important in the development of UPSC. To compare the genetic changes in OPSC with those in UPSC, seven microsatellite repeat polymorphisms were used to evaluate LOH in primary OPSC specimens. Allelic intensity was compared between normal and tumor DNA from microdissected, formalin-fixed, paraffin-embedded specimens. In addition to the same seven 1p markers used for UPSC, three additional non-1p markers for chromosomes 1q, 11q, and 2p were tested to determine a baseline rate of LOH. RESULTS: Overall, 26.6% (8/30) of OPSC (vs 63.2% of UPSC) were characterized by loss at either of the two loci that define the critical region for UPSC. Rates of LOH at each of the 1p loci in the OPSC tumors ranged from 5.6 to 38.9%, which are compatible with background rates of loss for OPSC. LOH at non-1p loci was 29.2%. CONCLUSION: While a tumor suppressor gene on 1p appears to be an important genetic event in the development of UPSC, a similar rate and pattern of loss on 1p are not identified in OPSC. Thus, despite the striking clinical similarities between UPSC and OPSC, tumorigenesis in these carcinomas appears to occur via distinctly different pathways.     

Microsatellite analysis in serous tumors of the ovary.

Thirty-four serous ovarian neoplasms were analyzed for microsatellite instability (MIN) and loss of heterozygosity (LOH) at 20 chromosomal loci of eight different chromosomes, including the map positions of the six known mismatch repair genes. Twelve of the 20 (60%) serous ovarian tumors of low malignant potential (LMP) and 13 of 15 (87%) samples of serous ovarian carcinomas, taken from 14 patients, showed LOH at one or more of the analyzed microsatellite loci. In serous carcinomas, LOH of the dinucleotide repeat D7S521 was most frequent. Six of 20 (30%) LMP tumors were also affected by MIN at more than one locus, whereas in the carcinomas MIN was found only sporadically (p < 0.025). No correlation between increased occurrence of MIN and LOH at the chromosomal loci of the known mismatch repair genes were discovered for these LMP tumors. Although our observation regarding LOH frequency in serous LMP tumors and serous carcinomas is compatible with the hypothesis that serous LMP tumors might represent precursor lesions of invasive carcinomas, the results concerning the occurrence of MIN suggest that the mechanisms of tumorigenesis of some tumors of LMP are distinct from those in invasive serous carcinomas.