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Clinical Cancer Research Vol. 11, 7651-7657, November 1, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Whole-Genome Allelotyping Identified Distinct Loss-of-Heterozygosity Patterns in Mucinous Ovarian and Appendiceal Carcinomas

Colleen M. Feltmate1, Kenneth R. Lee2, Michael Johnson1, John O. Schorge6, Kwong-kwok Wong7, Ke Hao3, William R. Welch4, Debra A. Bell5, Ross S. Berkowitz1 and Samuel C. Mok1

Authors' Affiliations: 1 Department of Obstetrics, Gynecology, and Reproductive Biology, Division of Gynecologic Oncology; 2 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; 3 Department of Biostatistics, Harvard School of Public Health; 4 Department of Pathology, Massachusetts General Hospital; 5 Gillette Center For Women's Cancer, Dana-Farber Cancer Institute, Boston, Massachusetts; 6 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Texas Southwestern Medical School, Dallas, Texas; and 7 Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Colleen M. Feltmate, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-3344; E-mail: cfeltmate{at}partners.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Mucinous adenocarcinoma of the ovary is one of the common histologic types of ovarian cancer. Its pathogenesis is largely unknown. In addition, the differential diagnosis of metastatic mucinous carcinomas to the ovaries, particularly those originating from the appendix, remains challenging. The purpose of this study is to identify molecular biomarkers for mucinous ovarian adenocarcinoma and compare them with those of appendiceal origin.

Experimental Design: Genome-wide loss-of-heterozygosity (LOH) analysis was done on DNA isolated from 28 microdissected primary mucinous ovarian carcinomas and five appendiceal adenocarcinomas. Markers from high-loss regions were selected for further analysis on a total of 32 ovarian and 14 appendiceal cancers.

Results: High levels of LOH rates (>40%) were detected on chromosome arms 9p, 17p, and 21q in mucinous ovarian carcinoma cases. The frequency of allelic loss was similar between high-grade and low-grade mucinous ovarian carcinoma cases but was significantly higher in ovarian versus appendiceal cases. In addition, LOH rates on five chromosomal loci were statistically different between ovarian and appendiceal carcinomas.

Conclusion: A high frequency of LOH can be found in mucinous ovarian adenocarcinomas independent of grade. Despite histologic similarities between mucinous ovarian carcinomas and metastatic appendiceal carcinomas, they have distinct LOH profiles, which may be used for distinguishing the two diseases.

Mucinous ovarian carcinomas exhibit unique histologic characteristics, which may provide insight into their natural history. They are usually large, unilateral, smooth surfaced, multilocular, or unilocular cystic and solid masses containing watery or viscous mucoid material. Histologically, mucinous epithelia of different degrees of atypia (benign, borderline, or malignant) are commonly present within the same tumor, often juxtaposed. In fact, Puls et al. were able to identify benign epithelium adjacent to malignant epithelium in 90% of mucinous tumors and were able to define an area of transition from benign to markedly atypical epithelium in at least 50% of cases (1).

Clinically, metastatic mucinous carcinomas, originating in the appendix, small intestine, pancreas, biliary tract, stomach, or cervix (2–6), may involve the ovaries and present clinically as a primary ovarian tumor. An accurate diagnosis of a mucinous ovarian carcinoma involving the ovary is critical for proper patient care. Features that favor a primary mucinous carcinoma are large size, unilaterality, an expansile pattern of invasion, a complex papillary pattern, and coexisting benign and borderline epithelium (7). Features favoring a metastatic mucinous carcinoma are bilaterality, spread beyond the ovary, a multinodular growth pattern, surface involvement, and vascular space invasion (7).

The distinction between primary and secondary mucinous ovarian carcinomas is crucial clinically, in that the prognosis of primary ovarian mucinous carcinomas confined to the ovary is very good, whereas metastatic mucinous tumors are associated with a poor prognosis. Among all primary sites for metastatic mucinous carcinomas, the appendix is the least common (8, 9). Because it is uncommon, the clinical use of radical tumor cytoreduction and chemotherapy is uncertain. Nevertheless, because it accounts for 20% of the nongenital tract primary tumors metastasizing to the ovary (10), appendiceal adenocarcinoma should be considered by gynecologic oncologists in the differential diagnosis of an intra-abdominal mass and ascites. The ability to differentiate between an ovarian and appendiceal primary is critical as the treatment modalities vary (8).

Loss-of-heterozygosity (LOH) analyses of solid tumors have not only enabled the delineation of specific minimally lost regions as the likely locations of critical tumor suppressor genes but also provided the molecular portrait of the pattern of accumulation of genetic alterations in a multistep progression of cancer (11–16). The use of available LOH data as markers for diagnosis and prognosis of cancer has also become generally accepted. A higher frequency of consistent LOH at defined chromosomal regions critical for specific cancers has made this a useful, reliable DNA marker for diagnosis and prognosis of cancer, regardless of whether the target gene has been identified (17, 18). In this study, we applied a genome-wide LOH analysis on DNA isolated from microdissected primary mucinous ovarian carcinomas and compared the profile with that of appendiceal carcinomas to identify molecular markers that may differentiate these two diseases.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 References
 
Specimen collection. Tumor specimens were collected from the Brigham and Women's Hospital, Massachusetts General Hospital, University of Texas Southwestern Medical Center, and the Cooperative Human Tissue Network. All specimens were diagnosed based on the WHO and the International Federation of Gynecology and Obstetrics criteria. All ovarian and appendiceal tumor tissues were collected from primary ovarian and appendiceal sites, respectively. In appendiceal cases where there was disease in both the appendix and the ovary, only the appendix was used for microdissected tumor DNA. Corresponding normal tissues were also collected from uninvolved organs removed during surgery. All tissue specimens were collected and archived under protocols approved by the internal review board of the parent institutions.

For fresh frozen sections, fresh specimens were embedded in Tissue-Tek optimum cutting temperature medium (Miles, Elkhart, IN), snap-frozen in liquid nitrogen, and stored at –80°C until use. The archival tissues in paraffin blocks were retrieved from pathology files in the Laboratory of Gynecologic Oncology at the Brigham and Women's Hospital. Clinical and pathologic characteristics for all cases are summarized in Table 1.


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  		Table 1. Clinicopathologic characteristics of patients with mucinous ovarian and appendiceal adenocarcinomas

 
Microdissection and whole-genome amplification. Frozen sections (7 µm) were cut using a cryostat and mounted on a PENfoil slide. They were immediately fixed in 70% ethanol for 30 seconds, stained with 1% methyl green for 5 seconds, and washed in distilled water. Paraffin sections (7 µm) were cut using a microtome. Sections on PENfoil slides were deparaffinized in xylol for 2 minutes. A descending series of ethanol was used: 100% x 2, 30 seconds; 95% x 2, 30 seconds; 70%, 10 seconds; distilled water, 10 seconds. They were stained as above, washed in distilled water, and air-dried. Microdissection was done using a Leica LMD system as described (19). DNA was then extracted and purified by the QIAamp DNA Micro Kit according to the manufacturer's instruction (Qiagen, Inc., Valencia, CA).

Whole-genome amplification was done on the purified DNA by the Genomiphi DNA amplification system according to the manufacturer's instruction (Amersham Biosciences, Piscataway, NJ). Amplified DNA was further purified by the QIAamp DNA Micro Kit (Qiagen).

Loss-of-heterozygosity analysis. A total of 200 ABI PRISM Linkage Mapping Set fluorescent microsatellite markers (Applied Biosystems, Foster City, CA), spanning all nonacrocentric autosomal arms and both arms of chromosome X, were used in the initial screening on 28 mucinous ovarian carcinomas and five appendiceal carcinomas. These primers were obtained from markers that were evenly distributed on all chromosomes with an average of 20-cM genetic distance. Cytogenetic location of the markers was determined by data obtained from the following four web sites including Genome Database (http://www.gdb.org), University of California at Santa Cruz' Genome Browser (http://genome.ucsc.edu), National Center for Biotechnology Information's Map Viewer (http://www.ncbi.nlm.nih.gov/genome/guide), and Ensemble (http://www.ensembl.org). A total of 55 markers that showed >30% LOH rate either in the ovarian or appendiceal carcinomas were selected and LOH analysis was done on an additional nine mucinous appendiceal carcinoma cases and four mucinous ovarian carcinoma cases. PCR reactions were done in a 10-µL volume as described (19). Amplified PCR products for multiple loci were pooled and run on an ABI PRISM 310 automated capillary electrophoresis DNA sequencer (Applied Biosystems).

The allelic products were assessed for peak height and peak area using Genescan (version 3.1) and Genotyper software (version 3.6; Applied Biosystems), and the ratios of heterozygous normal and tumor alleles were calculated as described previously (19). LOH was called if the effective decrease in one allele was >50% (normal: tumor allelic ratios, <0.5 or >2.0). Values between 0.5 and 2.0 were scored as retention of heterozygosity. A unique peak in both the tumor cells and nontumor cells was scored as homozygosity or not informative. Each allele assignment was also confirmed manually.

Statistical analysis. LOH analysis was done by dCHIP functions (20). Pearson's {chi}2 or Fisher's exact analyses were used to identify markers that distinguished mucinous ovarian tumors from appendiceal tumors. The frequencies of allelic loss (FAL) were compared between different groups by Mann-Whitney test. Statistical algorithms were from SPSS 10.0 for Windows software (SPSS, Inc., Chicago, IL). Probability value was two tailed, with P < 0.05 regarded as statistically significant.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
A total of 200 ABI PRISM Linkage Mapping Set fluorescent microsatellite markers (Applied Biosystems), spanning all nonacrocentric autosomal arms and both arms of chromosome X, were used in the initial screening of DNA isolated from 28 microdissected mucinous ovarian carcinomas (Fig. 1). High levels of LOH rates (>40%) were detected on chromosome arms 9p, 17p, and 21q in mucinous ovarian carcinoma cases (Fig. 2). The FAL for each case was determined and compared between high-grade and low-grade mucinous ovarian carcinoma cases and ovarian and appendiceal cases. The results showed that there was no significantly difference in FAL between high-grade (varied 11-57%) and low-grade (varied 10-37%) ovarian mucinous carcinoma cases (P = 0.43; Fig. 3). However, appendiceal carcinomas showed significantly lower FAL than that of ovarian carcinomas (P = 0.016).



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  		Fig. 1. Genome-wide LOH analyses of mucinous ovarian adenocarcinomas using dCHIP functions (20). Column, one tumor sample; row, microsatellite marker, whose name is labeled on the right margin of the blue, LOH; yellow, retention; white, noninformative. Score, blue, recurrence rate of LOH.

 


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  		Fig. 2. Average LOH rates on each chromosome arm in 28 mucinous ovarian adenocarcinomas.

 


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  		Fig. 3. Comparison of FAL among low-grade and high-grade ovarian carcinomas and appendiceal carcinomas. The box is bounded above and below by the 75th and 25th percentiles, and the median is the line in the box. Whiskers are drawn to the nearest value not beyond a standard span from the quartiles; points beyond (outliers) are drawn individually, where the standard span is 1.5x (interquartile range).

 
In mucinous ovarian carcinomas, multiple minimally deleted regions, which showed >40% LOH rates, were identified (Fig. 1). They were located on 1p36.2-36.3, 1p13.3-22.3, 1q31.2-31.3, 3p25, 3q26.32, 4q24, 5q31.2, 6q25.2, 8p22-23, 9p22.1, 9p24.3, 9q22.31, 10p15, 11q23-24, 14q11.2, 14q32, 15q26, 16p13.2, 17p13.3, 17p12-11.2, 18q12.1, 19q13.2, 20p12.3, 20q13.1, Xp22.3, and Xq28.

Based on the data obtained from the initial genome-wide allelotyping on 28 ovarian and five appendiceal carcinomas, a total of 55 markers that showed >30% LOH rate either in the ovarian or appendiceal carcinomas were selected, and LOH analyses were done on four additional mucinous ovarian carcinoma cases and nine additional appendiceal cases. The LOH rates on these 55 markers in a total of 32 ovarian carcinoma cases were then compared with that of 14 appendiceal carcinoma cases (Table 2). The results showed that mucinous ovarian carcinomas had significantly higher LOH rates at locus D1S413 on chromosome 1q31.2-31.3 (P = 0.0018), locus D6S1574 on chromosome 6p21.1 (P = 0.0321), and locus D9S285 on chromosome 9p22.1 (P = 0.0054) than that of mucinous appendiceal carcinomas. On the other hand, mucinous appendiceal carcinomas had significantly higher LOH rates at locus D6S462 on chromosome 6q21 (P = 0.0183) and locus DXS1226 on chromosome Xp11.4 (P = 0.0366) than that of mucinous ovarian carcinomas. Multiple genes have been mapped to these loci and they have been shown to be involved in various signaling pathways (Supplementary Table).


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  		Table 2. LOH analyses of mucinous ovarian and appendiceal adenocarcinomas

 
Among appendiceal cancer cases, seven had ovarian involvement. FALs in this group were compared with that without ovarian involvement. However, statistical difference in FAL was not detected between these two groups. Furthermore, low rates (<5%) of microsatellite instability were detected in both ovarian and appendiceal cancers. No statistical difference was found between the two groups.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Mucinous ovarian carcinoma is uncommon, accounting for <5% of all ovarian carcinomas (21). Due to the low incidence, there has been a lack of availability of tissue specimens. Heterogeneity of the tumor tissue has also been an impediment. Thus, significant genetic changes in mucinous ovarian carcinomas, aside from K-RAS and TP53 mutations, have not been reported. Suzuki et al. identified a 50% K-RAS mutation rate in 26 unmicrodissected mucinous ovarian cancer cases compared with 5% in serous ovarian carcinomas (22). They also found 23% LOH rate in 6q27, which was significantly lower than 53% identified in serous cancer (22). High K-RAS mutation rates were also found in mucinous borderline and invasive ovarian carcinomas (23, 24). Ikeda et al. (25) and Wertheim et al. (26) identified one of seven and two of five mucinous ovarian carcinomas, respectively, with TP53 mutation. LOH studies on a small number of cases have been reported on chromosomes 3, 5, 6, and 17 in multiple studies (22, 27, 28). However, significant differences between mucinous and other histologic types of ovarian cancer have not been described due to the limited number of cases studied. We report here the first genome-wide LOH study done on DNA isolated from 28 microdissected mucinous ovarian carcinoma cases. This study identified high LOH rates (>40%) on chromosome arms 9p, 17p, and 21q. High frequencies of LOH on chromosome arms 4p, 5q, 6q, 7p, 8p, 9q, 12q, 13q, 14q, 15q, 17p, 17q, 18q, 21q, and 22q have been reported in serous adenocarcinoma of the ovary (29, 30). Comparing our findings with those reported for serous ovarian cancer, we found that mucinous carcinomas have a unique LOH pattern with significantly higher LOH rates on 9p, particularly on 9p22.1 and 9p24.3 with 80% and 62% LOH rate, respectively. These data suggest that 9p LOH may be important for the pathogenesis of mucinous ovarian carcinomas.

Most studies of loss of chromosomal loci in ovarian cancers have revealed significantly higher LOH rates in high-grade serous carcinomas than that in low-grade serous carcinomas (28, 31). Interestingly, our data showed that both low-grade and high-grade mucinous carcinomas had comparable LOH rates. These results further support the notion that whereas low-grade and high-grade serous carcinomas may have different pathogenetic pathways, low-grade and high-grade mucinous carcinomas may represent a continuum in tumor progression.

Appendiceal adenocarcinoma is a rare cancer and constitutes <0.5% of all gastrointestinal neoplasms (32). Because there are no specific or early symptoms, it is very difficult to diagnosis preoperatively. Most female patients are diagnosed as having gynecologic diseases due to the frequent occurrence of ascites and/or pelvic masses (33). It is very difficult to make a correct diagnosis even intraoperatively, particularly when the ovaries are involved. However, the ability to differentiate between an ovarian and appendiceal primary is critical as the treatment modalities vary (8). In addition, the tumors may be difficult to distinguish histologically. Various immunohistochemical stains have been shown to aid in this differential. It has been reported that appendiceal or colorectal carcinomas are diffusely positive for CK20 (100%) and often negative for CK7 (71%) but were often positive for MUC5AC (86%) and Dpc4 (100%). Even when primary ovarian and metastatic appendiceal or colorectal carcinomas shared expression of both CK7 and CK20, they could usually be distinguished by the pattern of positivity (diffuse CK7 and patchy CK20 in ovarian tumors and patchy CK7 and diffuse CK20 in appendiceal tumors; ref. 34).

Only a few genetic analysis studies have been done on primary ovarian and appendiceal mucinous carcinomas. Using markers on three chromosomal loci, Chuaqui et al. did a LOH study on 12 synchronous ovarian and appendiceal mucinous carcinomas and found differential patterns in some of the cases suggesting that they may represent separate primaries (35). Both ovarian and appendiceal mucinous carcinomas showed comparable K-RAS mutational rates (36). In this study, the majority of appendiceal cancer cases were obtained from patients with late-stage disease. In the current study, using the tumors from the primary appendiceal site, we show for the first time, that appendiceal mucinous carcinomas have significantly lower allelic loss frequencies compared with that of ovarian mucinous carcinomas, suggesting that appendiceal carcinomas have a relatively more stable genome. Furthermore, using whole-genome genotyping, we identified LOH rates in five loci located on chromosomes 1q31.2-31.3, 6p21.1, 9p22.1, 6q21, and Xp11.4 that were statistically different between ovarian and appendiceal carcinomas, suggesting that these two tumor types have distinct pathogenetic pathways. Although significant differences in LOH rates exist on specific chromosomal loci, further studies validating these data would be needed before using these loci as molecular markers. The involvement of those genes located in these candidate loci in the pathogenesis of either mucinous ovarian or appendiceal cancers warrants further investigation.

In conclusion, LOH is less frequent and involves different chromosomal loci in mucinous ovarian carcinomas compared with its serous counterpart. Furthermore, despite histologic similarities between mucinous ovarian and metastatic appendiceal carcinomas, they have distinct LOH profiles. Additional validation studies with larger sample sizes are needed to establish the significance of these loci as molecular markers for these two diseases.


   Footnotes
 
Grant support: Dana-Farber/Harvard Ovarian Cancer Specialized Programs of Research Excellence grant P50CA165009; NIH grant R33CA103595; Department of Health and Human Services; Gillette Center for Women's Cancer; Adler Foundation, Inc.; Edgar Astrove Fund; Ovarian Cancer Research Fund, Inc.; the Morse Family Fund; Natalie Pihl Fund; Ruth N. White Research Fellowship; and Friends of Dana-Farber Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

Received 5/ 9/05; revised 7/ 5/05; accepted 8/ 4/05.


   References
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 Abstract
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 Discussion
 References
 

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