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Clinical Cancer Research Vol. 7, 831-838, April 2001
© 2001 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

The p53 Mutational Spectrum Associated with BRCA1 Mutant Ovarian Cancer1

Richard E. Buller2, Thomas A. Lallas, Mark S. Shahin, Anil K. Sood, Melanie Hatterman-Zogg, Barrie Anderson, Joel I. Sorosky and Patricia A. Kirby

Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology [R. E. B., T. A. L., M. S. S., A. K. S., M. H-Z., B. A., J. I. S.] and Pathology [P. A. K.], The University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242-1009


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Cancer-specific p53 mutational spectra have been identified. Data from murine models and human BRCA1-related hereditary breast cancers suggest that both unique and specific BRCA1-associated p53 mutations may be found in BRCA1-related ovarian cancers.

Experimental Design: The p53 mutational spectrum from ovarian cancers containing either somatic or germ-line BRCA1 mutations was compared with that of sporadic ovarian cancers defined as those diagnosed with a negative family history for breast/ovarian cancer in a three-generation pedigree. Tumor DNA was screened over exons 2–11 of the p53 gene by the PCR and single-strand confirmation polymorphism analysis of the amplimers. Cycle-based DNA sequencing from separate reactions was used to confirm p53 mutations.

Results: p53 gene mutations were detected in 42 of 86 sporadic ovarian cancers, compared with 13 of 15 cancers with somatic BRCA1 mutations (P = 0.007) and 16 of 20 cancers with germ-line BRCA1 mutations (P = 0.01). p53 null mutations were found in 31.4% of BRCA1 mutant cancers, compared with only 9.3% of the sporadic cancers (P = 0.002). The p53 mutational spectrum of germ-line BRCA1-related cancers was shifted toward transversions, frameshifts, and non-CpG transitions relative to the spectrum of sporadic ovarian cancers. Thirty-three unique ovarian cancer p53 mutations were sequenced. However, the specific p53 mutations in the BRCA1 mutant cancers were no more unique to this cohort than the p53 mutations of the sporadic cancers.

Conclusions: Ovarian cancers containing somatic or germ-line BRCA1 mutations are uniformly accompanied by p53 dysfunction. This finding offers additional support to observations regarding the importance of p53/BRCA1 interactions in ovarian carcinogenesis.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mutation of the p53 tumor suppressor gene is one of the most frequent molecular genetic events in cancer (1, 2, 3) . Characteristic p53 mutational spectra have been described for Burkitt’s lymphoma (4) , aflatoxin-induced hepatocellular carcinoma (5) , benzo(a)pyrene-induced lung cancers (6) , and skin cancers where UV light is causal (2 , 7) . Several reports suggest that novel p53 mutations and an overall high frequency of the p53 mutations associate with familial (8) and hereditary (9, 10, 11) breast cancers. There are few reports of p53 mutations in BRCA1-related ovarian cancers (12, 13, 14, 15) . The total number of BRCA1 mutant cancers analyzed is 46. Each report has limitations, such as evaluating a single ethnic group, Ashkenazi Jews, without a control population (12) , evaluation only of primary peritoneal carcinomas (13) , and major failures of tumor DNA to amplify in some PCR reactions (15) .

A growing body of evidence suggests that p53 and BRCA1 interact directly (16, 17, 18) and may play an important role in the DNA repair process (19, 20, 21, 22, 23, 24, 25, 26, 27, 28) . Other studies have demonstrated the potential for proliferative advantages to cells simultaneously null for both p53 and BRCA1 function (29 , 30) . Taken together, these observations suggest that additional studies of p53 mutations associated with hereditary ovarian cancers may be useful for several reasons: (a) if unique ovarian cancer p53 mutational patterns do exist, their characterization may facilitate identification of potential germ-line BRCA1 carriers for targeted direct BRCA1 sequencing; and (b) there has been debate regarding survival of individuals with BRCA1-associated cancers (31, 32, 33, 34, 35) . Because p53 mutations may also influence ovarian cancer survival (36) , selection of control groups matched for p53 mutation status and potentially for p53 mutation type may be critical to most appropriately address this issue. To these ends, we have recently completed screening of ~150 ovarian, primary peritoneal, and fallopian tube carcinomas3 for BRCA1 null mutations using a protein truncation assay (37) . The present study reports the relationship of p53 mutations in this group stratified for the presence or absence of BRCA1 mutation. Individuals with any family history of breast or ovarian cancer in which we did not identify a BRCA1 mutation were excluded in the beginning to minimize the confounding factors of BRCA2 or other, as yet undiscovered, hereditary ovarian cancer genes interacting with p53 as well as potential differences of p53 expression in familial ovarian cancers.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All samples were procured in accordance with the Institutional Committee for the Protection of Human Subjects. The methods used to isolate and screen genomic DNA as well as to characterize p53 mutations have been published previously (38, 39, 40) . Approximately 73% of the samples were from snap frozen samples, whereas 27% of the cancer DNA was isolated from paraffin-embedded tissue. Briefly, each exon in the open reading frame is PCR amplified, and the amplimers were analyzed by SSCP4 analysis on 6% polyacrylamide gels. Each gel contains positive and negative controls as well as a nondenatured sample. A mutation is inferred from shifts in banding patterns. When a shift is found, a separate PCR reaction is used to generate a product for cycle-based sequencing using the fmol system (Promega Corp., Madison, WI). Bidirectional sequencing identifies mutations that are subsequently resequenced from a third PCR reaction. Therefore, the evidence to support the presence of each mutation is generated from three independent reactions. Tumor expression of p53 was determined by DO7 antibody staining as we have described (41) . However, we do not use immunostaining to screen for p53 mutations because this method does not detect most p53 null mutations (39) . Overall, ~10% of ovarian cancers overexpress p53 in the absence of mutation, whereas 19% of mutations are D07 antibody negative. All immunopositive, SSCP-negative tumors have been completely sequenced (36) . Mutations are categorized as follows: transitions, purine <--> purine or pyrimidine <--> pyrimidine at CpG or non-CpG sites; transversions, purine <--> pyrimidine; or insertion/deletion.

Identification of tumor BRCA1 mutations was facilitated both by modified SSCP screening of all exons and splice junctions as we have described (42) and more recently by the PTT. The latter technique required snap frozen tissue and only identifies BRCA1 null mutations. Results of direct comparison of SSCP and PTT screening are the subject of a separate report.3 The BRCA1 mutant tumors included 6 with missense mutations detected by SSCP screening (43) and 29 protein-truncating mutations, of which 16 have been reported by our group (43) . Tumors were not consecutive. They were initially selected as we have described (43) and more recently were selected on the basis of available snap frozen tissue and loss of heterozygosity at the BRCA1 locus determined with the intragenic markers D17S 855, D17S 1322, and D17S 1323 (44) . This approach was chosen because we and others have found that tumor BRCA1 mutations are almost universally accompanied by loss of heterozygosity. All sporadic ovarian cancers in this study were screened for BRCA1 mutations either by SSCP (paraffin-embedded samples) or both SSCP and PTT (snap frozen tissue). In each case when a tumor with a candidate BRCA1 mutation was identified, genomic sequencing of the appropriately selected BRCA1 region was carried out. All mutations were verified from repeat PCR reactions and bidirectional sequencing as we have done traditionally to detect p53 mutations (39) . Once a tumor BRCA1 mutation was sequenced, a germ-line mononuclear cell DNA sample from the same individual was also sequenced over the identical region of the BRCA1 gene to determine whether the tumor mutation was a hereditary germ-line BRCA1 mutation or simply a somatic mutation, absent in the germ-line. PTT screening, of course, will not detect BRCA1 missense mutations. However, until a functional BRCA1 assay is developed, the significance of BRCA1 missense mutations is open to question. Furthermore, nearly 80% of the BRCA1 mutations reported in the Breast Cancer Information database are null mutations.5

Sporadic ovarian cancers were defined after a negative BRCA1 screening assessment and by omitting any individuals with a family history of breast or ovarian cancers in first-, second-, or third-degree relatives. Complete pedigree analysis with histological confirmation and/or death certificate review for the majority of the reported cancers among family members of study probands is part of the University of Iowa Hospital and Clinics Gynecological Oncology Tissue Bank record. For this assignment, we required a minimum of 10 female relatives >30 years of age in a three-generation pedigree (40) . This methodology was designed to eliminate familial ovarian cancers as a potential confounding variable for this study.

Statistical Analysis.
Categorical variables were tested by the {chi}2 statistic. Differences in means between continuous variables were analyzed by the t-statistic (two tailed). P < 0.05 was considered statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ovarian, primary peritoneal, and fallopian tube carcinomas were analyzed for p53 mutations from 86 probands with sporadic ovarian cancer and 35 different individuals whose tumors were found to harbor BRCA1 mutations. The BRCA1 mutant cancers included 20 germ-line and 15 somatic mutations. Table 1Citation summarizes the characteristics of each study cohort with respect to age of diagnosis, distribution by cancer site, FIGO stage (45) at presentation, histology, tumor grade, and DO7 antibody staining. Although the mean age at diagnosis for carriers of germ-line BRCA1 mutations, 54.9 years, was >5 years younger than for individuals with sporadic ovarian cancer, 60.2 years, a number of individuals with BRCA1-associated cancers were diagnosed in their 70s; therefore, this difference did not achieve statistical significance. As might be expected, the mean age at diagnosis for individuals with somatic BRCA1 tumor mutations, 60.1 years, was identical to that of individuals with sporadic cancers. Most of the BRCA1 mutations were associated with ovarian rather than peritoneal or fallopian tube cancers. Several differences between these groups are noteworthy. Tumors with any BRCA1 mutation were less likely to be diagnosed as FIGO stage I disease ({chi}2, 4.13; P = 0.04). They were also more often of higher histological grade, i.e., grade 2 or 3 ({chi}2, 4.92; P = 0.03). The highest incidence of grade 3 cancers (80%) was found in the germ-line mutant BRCA1 cohort. Comparison of all histological subtypes simultaneously showed no differences between groups. However, grouping the more prevalent types such as ANOS versus other histologies, or ANOS versus papillary serous, versus all other histologies revealed that ANOS was more prevalent in tumors with somatic BRCA1 mutations ({chi}2, 5.10; P = 0.02). In general, transitional carcinomas of the ovary are relatively uncommon. Nonetheless, two cases were reported in germ-line BRCA1 carriers (2 of 20; 10%) versus two cases (2 of 86; 2.3%) in individuals with sporadic ovarian cancers (P > 0.05). There were no differences in the frequency of DO7 antibody-positive cells between groups.


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  		Table 1 Histopathological features of tumors analyzed for p53 mutations

 
Fig. 1Citation , left, shows a representative SSCP analysis. Fig. 1Citation , right, shows the sequence of a representative p53 mutation from an individual carrying a germ-line BRCA1 mutation (2457 C->T stop 780). In this case, a p53 GAC to CAC transition mutation is seen in tumor DN but not in germ-line DNA. The specific p53 mutations associated with the study cancers are listed in Table 2Citation Citation . Overall, only 42 of the 86 sporadic cancers (48.8%) contained p53 mutations. In contrast, 13 of 15 cancers with somatic BRCA1 mutations (86.7%; {chi}2, 7.37; P = 0.007) and 16 of 20 cancers in germ-line BRCA1 carriers (80%; {chi}2, 6.36; P = 0.01) contained p53 mutations. The frequency distribution of p53 mutations by exon is listed for each cohort in Fig. 2Citation . p53 mutations in sporadic ovarian cancers were found throughout the open reading frame except within exons 3 and 11. More than half of the mutations were concentrated in exons 5 and 8. p53 mutations in somatic BRCA1 mutant cancers were found in exons 5–9 with >78% concentrated in exons 5 and 7. In contrast, the p53 mutations found in individuals carrying germ-line BRCA1 mutations were more uniformly distributed throughout exons 4–9. Slightly >70% occurred in exons 6–8. A single tumor in each group was found to contain two different p53 mutations.



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  		Fig. 1. Left, representative SSCPs from exons 8 and 7 of the p53 gene. ND, nondenatured sample. Abnormalities are seen for tumors 25, 178, and 320 in exon 8 and for tumor 20 in exon 7. In each case, a mutation has been sequenced. Positive and negative controls for each exon are on a portion of the gel not shown here. Right, comparison of exon 8 sequence between normal (N) and tumor tissue (T, top label) for proband 15.R. The sequence is from an antisense sequencing primer and reads forward from top to bottom. Arrow, G -> C base change in the tumor rendering codon 281 GAC to CAC or Asp to His.

 

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  		Table 2 Spectrum of p53 mutations in ovarian cancers

 

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  		Table 2A Continued

 


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  		Fig. 2. Distribution of p53 mutations by exon for the sporadic (n = 43), somatic BRCA1 mutant (n = 14), and germ-line BRCA1 mutant ovarian cancer (n = 19). For the percentage calculation, the number of exon-specific mutations is divided by n, the number of mutations in each cohort. x100.

 
Table 3Citation summarizes the p53 status of the cancers analyzed. Mutations were classified as transition at CpG sites or non-CpG sites, transversion, or frameshift. Tumors with wild-type p53 status were subclassified on the basis of their DO7 antibody staining characteristics. When the three cohorts were analyzed pairwise in contingency tables, significant differences between sporadic versus germ-line BRCA1 mutant ({chi}2, 13.7; P = 0.02) and sporadic versus any BRCA1 mutation ({chi}2, 15.9; P = 0.009) groups were found. In addition, if DO7 antibody-positive, p53 mutation-negative tumors are combined with all p53 mutation-positive tumors, the frequency of any p53 dysfunction is estimated at only 62.8% for sporadic cancers but 93.4% for somatic BRCA1 mutant cancers ({chi}2, 5.40; P = 0.02) and 90.0% ({chi}2, 5.50; P = 0.02) when there is a concomitant germ-line BRCA1 mutation. Eighty % of the DO7 antibody-positive tumors with wild-type p53 sequence based upon complete sequencing was found in individuals without any family history of breast or ovarian cancer. Thus, the mechanism that gives rise to overexpression of wild-type p53 may be relatively unique to sporadic ovarian cancers. Non-CpG transitions, transversions, and frameshift mutations were 1.6 (P = not significant), 2.3 ({chi}2, 5.21; P = 0.02), and 4.3 ({chi}2, 5.48; P = 0.02) times more common in the ovarian cancers of germ-line BRCA1 carriers than in sporadic ovarian cancers. The incidence of CpG transitions was only 5% for germ-line BRCA1 mutant cancers compared with a 20% rate in somatic BRCA1 mutant cancers and a 14% rate in sporadic ovarian cancers with wild-type BRCA1. These differences did not reach statistical significance. p53 null mutations can result either from insertion/deletion (frameshift) mutations or from nonsense point mutations. Overall, 8 of 86 (9.3%) sporadic ovarian cancers contained p53 null mutations. However, 11 of 35 (31.4%) of the BRCA1 mutant cancers and 8 of 20 (40%) of the germ-line BRCA1 cancers contained p53 null mutations ({chi}2, 9.20; P = 0.002 and {chi}2, 11.93; P = 0.0006, respectively). Thus, the combination of simultaneous p53 and BRCA1 null ovarian cancers was found to be particularly prevalent.


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  		Table 3 Classification of p53 mutation status

 
To determine whether the p53 mutations associated with BRCA1 mutant cancers were unique, we evaluated the frequency of the specific p53 mutations we sequenced relative to the frequency that each individual mutation has been reported to occur in ovarian cancer according to the Soussi database.6 Table 4Citation summarizes this analysis. Overall, 41 (55%) of the p53 mutations were either unique (n = 33) to our study or had only been reported once before (n = 8). This was true for 71% of the p53 mutations associated with germ-line BRCA1 tumors but also true for 55.6% of the sporadic ovarian cancers. Only one p53 mutation in the germ-line BRCA1 group had been reported as many as five times before, which contrasts with 11, or 26%, of the sporadic cancer p53 mutations and 5, or 35.7%, of the somatic mutant BRCA1 cancers.


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  		Table 4 Evaluation of specific p53 mutations and their frequencies

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Mutations in cancer arise through multiple mechanisms. Spontaneous deamination of methylcytosine at CpG sites gives rise to classical transition mutations (2 , 46 , 47) . These mutations are thought to occur at random throughout the genome. An accumulation of such events over an individual’s lifetime goes along with an increasing tendency to develop cancer as one ages. These observations would lead one to predict that sporadic ovarian cancers would be more likely to harbor CpG transition mutations and would occur at an older age than BRCA1-related cancers. Indeed, our germ-line BRCA1 ovarian cancers were diagnosed at an earlier age than the sporadic or somatic BRCA1 cancers, both of which were more likely to have p53 CpG transition mutations than were the germ-line BRCA1 cancers. However, the differences were not statistically significant, probably because of relatively small sample sizes when analyzed on the basis of individual mutation types. Non-CpG transitions, transversions, and frameshift p53 mutations were seen to occur at a higher frequency in the ovarian cancers of BRCA1 carriers. These differences did approach or achieve statistical significance. All three types of mutations were more common in ovarian cancers with concomitant BRCA1 mutation. p53 mutations in general were more likely to occur in BRCA1 mutant ovarian cancer ({chi}2, 11.9; P = 0.0006) than in sporadic cancers. The forces responsible for such shifts in the p53 mutational spectra of BRCA1-associated disease need to be elucidated to better understand the carcinogenic process in hereditary ovarian cancer.

To date, only four other studies have reported analysis of p53 mutations in BRCA1-related ovarian or peritoneal cancers (12, 13, 14, 15) . Similar studies of BRCA1 mutant breast cancers have also been sparse (9, 10, 11) . Most of these studies suffer from a variety of limitations, such as evaluating only the Ashkenazi population (10 , 12) , failure to include a comparable control population (12) , and small numbers of BRCA1 mutations precluding statistical analysis (14) . Only a single tumor with a somatic BRCA1 mutation had its p53 status determined (14) . Although the frequency of p53 mutations in BRCA1-related primary peritoneal carcinoma is as high as we have found (13) , the general consensus is to be careful in comparing mechanisms between ovarian and peritoneal carcinomas. Major p53 SSCP screening problems secondary to failure to amplify all or at least 50% of the exons limits the only other sizable study with an appropriate control population of sporadic ovarian cancers (15) . Nonetheless, there is a clear consensus between these studies, including the present work, that ovarian cancer BRCA1 mutation is nearly uniformly accompanied by p53 dysfunction. It is tempting to speculate that the 10% or so of tumors without p53 mutation or p53 overexpression may have a compromised p53 pathway attributable to p19ARF dysfunction.

p53 dysfunction in BRCA1 mutant ovarian cancers usually results from a mutation (12, 13, 14, 15) that can occur anywhere throughout the open reading frame in contrast to earlier suggestions (8 , 9) that a limited number of hot spots might exist. Our data do not rule out the possibility that rare p53 mutations, especially transversion or frameshift, are markers for BRCA1-related ovarian cancers as suggested by Armes et al. (48) . Unique p53 mutations, which may disassociate transformation suppression from other wild-type p53 functions, have been described recently (49) . A search of the Soussi database for comparison of the mutational spectrum of the Iowa ovarian cancers versus those of ovarian cancers reported in the literature provided a distinct caution to arrival at such a conclusion. Overall, many unique p53 mutations were characterized in our cohorts, regardless of their BRCA1 status. Thus, it is critical to provide appropriate controls from a population with an identical ethnic makeup rather than reporting isolated mutation frequencies.

Several lines of evidence suggest a potentially important interaction between BRCA1 and p53. Both proteins play a similar role in regulating cellular proliferation and have been implicated in DNA damage surveillance (19, 20, 21, 22, 23, 24, 25, 26, 27, 28) . There is significant homology between the BRCT domain (exons 16–22) of BRCA1 and 53PB1, a human p53 binding protein, as well as RAD9, a yeast protein that modifies cell cycle progression at both the G1 and G2 checkpoints (26) . Exciting direct evidence for p53/BRCA1 interaction has been reported by Zhang et al. (16) , who mapped the interacting regions: amino acids 224–500 of BRCA1 and the COOH-terminal domain of p53. In addition, embryonic lethal BRCA1 gene knockout experiments have shown decreased cellular proliferation and decreased expression of MDM2, which participates in a p53 feedback loop as well as binding to p53 protein (24 , 29) . Both p53 and p21/WAF are up-regulated under these conditions. Mouse embryos doubly mutant for p53 or p21 and BRCA1 survived longer, suggesting at least some proliferative advantage (29 , 30) . Mice heterozygous for BRCA1 mutation do not demonstrate an obvious predisposition to mammary or other cancers (50) . Consistent with these murine models, we have found that the frequency of p53 null mutations was increased in cancers with concomitant BRCA1 mutation (P = 0.002). Taken together, these data argue that early inactivation of p53 in association with BRCA1 mutation may offer a significant and critical tumor proliferative advantage that does not occur at random in ovarian carcinogenesis.


   ACKNOWLEDGMENTS
 
We thank Marisa Dolan, Sara McClain, Jenny Rathe, and Matthew J. Buller for expert technical assistance. Rebecca Sandersfeld and Linda Sanders provided assistance with manuscript preparation.


   FOOTNOTES
 
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.

1 This research was supported in part by the Florence and Marshall Schwid Award (to R. E. B.) from the Gynecological Cancer Foundation. Back

2 To whom requests for reprints should be addressed, at Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 200 Hawkins Drive, #4630 JCP, Iowa City, IA 52242-1009. Phone: (319) 356-2015; Fax: (319) 353-8363; E-mail: richard-buller{at}uiowa.edu Back

3 J. P. Geisler, M. A. Hatterman-Zogg, J. Rathe, T. Lallas, and R. E. Buller. Ovarian Cancer BRCA1 mutation detection: Protein truncation test (PTT) outperforms single strand conformation polymorphism (sscp) analysis, submitted for publication. Back

4 The abbreviations used are: SSCP, single-strand conformational polymorphism; PTT, protein truncation assay; FIGO, International Federation of Gynecology and Obstetrics; ANOS, adenocarcinoma not otherwise specified. Back

5 Internet address for the Breast Cancer Information Core: http://www.nchgr.nih.gov/intramural_research/lab_transfer/bic/index.html. Back

6 Internet address: http://perso.curie.fr/Thierry.Soussi/index.htm. Back

Received 8/28/00; revised 1/ 3/01; accepted 1/ 3/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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