Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival

  • Pedro Kringen1,
  • Yun Wang1, 2, 3,
  • Vanessa Dumeaux1, 5,
  • Jahn M Nesland4,
  • Gunnar Kristensen2,
  • Anne-Lise Borresen-Dale1, 3 and
  • Anne Dorum2Email author
BMC Cancer20055:134

DOI: 10.1186/1471-2407-5-134

Received: 14 January 2005

Accepted: 17 October 2005

Published: 17 October 2005

Abstract

Background

Ovarian carcinomas from 30 BRCA1 germ-line carriers of two distinct high penetrant founder mutations, 20 carrying the 1675delA and 10 the 1135insA, and 100 sporadic cases were characterized for somatic mutations in the TP53 gene. We analyzed differences in relation to BRCA1 germline status, TP53 status, survival and age at diagnosis, as previous studies have not been conclusive.

Methods

DNA was extracted from paraffin embedded formalin fixed tissues for the familial cases, and from fresh frozen specimen from the sporadic cases. All cases were treated at our hospital according to protocol. Mutation analyses of exon 2 – 11 were performed using TTGE, followed by sequencing.

Results

Survival rates for BRCA1-familial cases with TP53 mutations were not significantly lower than for familial cases without TP53 mutations (p = 0.25, RR = 1.64, 95% CI [0.71–3.78]). Median age at diagnosis for sporadic (59 years) and familial (49 years) cases differed significantly (p < 0.001) with or without TP53 mutations. Age at diagnosis between the two types of familial carriers were not significantly different, with median age of 47 for 1675delA and 52.5 for 1135insA carriers (p = 0.245). For cases ≥50 years at diagnosis, a trend toward longer survival for sporadic over familial cases was observed (p = 0.08). The opposite trend was observed for cases <50 years at diagnosis.

Conclusion

There do not seem to be a protective advantage for familial BRCA1 carriers without TP53 mutations over familial cases with TP53 mutations. However, there seem to be a trend towards initial advantage in survival for familial cases compared to sporadic cases diagnosed before the age of 50 both with and without TP53 mutations. However, this trend diminishes over time and for cases diagnosed ≥50 years the sporadic cases show a trend towards an advantage in survival over familial cases. Although this data set is small, if confirmed, this may be a link in the evidence that the differences in ovarian cancer survival reported, are not due to the type of BRCA1 mutation, but may be secondary to genetic factors shared. This may have clinical implications for follow-up such as prophylactic surgery within carriers of the two most frequent Norwegian BRCA1 founder mutations.

Background

Ovarian cancer is one of the leading causes of cancer-related death in women today. It is the 4th most common cancer in women in Norway and accounts for 5 – 6% of all cancers [1, 2]. Mean age at diagnosis for sporadic cases have been reported to 62.3 years [3], and in Norway to 65 years. Age-standardized incidence rates were 13.5 pr 100.000, and close to 40% of the patients is achieving 5-year survival according to The Norwegian Cancer Registry (OVANOR 1991 – 1996).

Almost 10% of epithelial ovarian cancer cases are associated with dominant genetic predisposition, in most cases (80 – 90%), linked to mutations in BRCA1 or BRCA2 [46]. Mean age at diagnosis for these inherited cases have been reported to be from 49 to 54.3 years [3, 7]. The penetrance of the disease in mutation carriers varies, and has been reported to be from 27 – 80% [810]. It should be noted that both the incidence rate for hereditary cases and the penetrance of the disease may differ depending on geographic and ethnic origin [11]. The survival rate may also vary depending on type and localization of the mutation. Some studies have reported that ovarian cancer patients carrying germ-line BRCA1 mutations have an enhanced survival rate compared to sporadic cases [3, 1214]. Other studies demonstrated only an initial survival advantage that disappeared with time, and concluded that no enhanced survival rates follows BRCA1 dysfunction [1517]. These studies predict a survival rate for BRCA1 familial ovarian cancer that is equal to or higher than non-familial cases.

Both the penetrance estimates and the survival rates are based on studies in populations with strong founder effects, and may therefore be biased. The type of mutation in the BRCA1 gene may affect the timing of the diagnosis of the disease, the response to environmental exposure causing DNA damage, the efficiency of DNA repair, and the frequency of somatic mutations developing in the tumor. These factors may in turn affect the survival rate.

Mutations in the TP53 tumor suppressor gene are the most common genetic alteration in human tumors and have been suggested as a molecular marker for prognosis. TP53 encodes a nuclear phosphoprotein located at chromosome region 17p13 involved in cell cycle arrest and DNA repair and somatic TP53 mutations are known to associate with familial ovarian cancer. In ovarian tumors from BRCA1 mutation carriers, somatic TP53 mutations are found in 60 – 80% of the cases [1822]. Thirty to 50% of all ovarian cancers have been reported to harbor a TP53 mutation [1820, 23, 24]. Further, in 30 – 85% of the sporadic ovarian carcinomas both a TP53 mutations and a somatic BRCA1/BRCA2 mutation have been found [18, 20, 25].

These findings implicate that TP53 and BRCA1 directly interacts and may play an important role in DNA repair processes and tumor suppression [26, 27]. However, despite the high frequency of mutations in the tumor suppressor gene TP53, there are several reports concluding that TP53 is not a good predictor of prognosis in sporadic ovarian cancer patients [24, 28, 29].

We have previously reported two Norwegian BRCA1 founder mutations; 1135insA [30] and 1675delA [11]. Carriers of these mutations show almost the same penetrance for ovarian- and breast cancer and the penetrance is also high compared to most reported BRCA1 mutation carriers. By age 50, 48% of mutation carriers had experienced breast- and/or ovarian cancer. Mean age of ovarian cancer diagnosis was ~55 years [10]. Three per cent of all Norwegian ovarian cancers are caused by either of the two founder mutations [31]. As a result of a clinical follow-up program for early diagnosis in women from breast-ovarian cancer kindreds, these two mutations may account for more than half of those with a BRCA1 mutation in Norway. The histopathological characteristics of both breast and ovarian cancer indicated an unfavorable prognosis in these mutation carriers [32].

In the present study, we have screened epithelial ovarian tumors from 30 familial cases and 100 sporadic cases for somatic mutations in the TP53 gene. The cancer treatment was according to our hospital protocol. The familial cases consisted of one group with the BRCA1 1135insA mutation and the other had the BRCA1 1675delA mutation [10]. The TP53 mutation status was correlated to survival, age at diagnosis and histopathological features.

Materials

Formalin fixed and paraffin embedded ovarian cancer tissue from 30 BRCA1 germ line mutation carriers were collected and used for DNA extraction. Of the familial cases 20 patients carried the 1675delA mutation and another 10 patients the 1135insA mutation, which is a representative distribution between the two mutations in the Norwegian population. The BRCA1 carriers were from families with at least two first-degree relatives, or second-degree relatives through male, with ovarian cancer and/or breast cancer under age 60. All cases were sampled from pedigree regardless of survival status, as ovarian cancer treatment is centralized to our hospital. Analysis of fresh frozen specimen of tumor DNA from the 100 sporadic cases sampled from 1992–2003, included in this study has previously been reported [29]. Both groups were diagnosed and treated at the Norwegian Radium Hospital according to protocol. The patient characteristics are shown in Table 1. All tumors were reviewed at our department of pathology, the familial tumors by our team pathologist, and were classified and graded according to the World Health Organization (WHO) criteria. Follow-up time for each case was calculated from the date of diagnosis up to date of death or end of study (15th April, 2004).
Table 1

Patient characteristics

 

Sporadic cases

BRCA1 carriers

  

All familial cases

1135insA

1675delA

No of cases

100

30

10

20

Age at diagnosis: Median

59

49

52.5

47

range

39 – 80

39 – 80

41 – 80

39 – 65

FIGO stage

    

I – II

9 (9.0%)

8 (26.7%)

2 (20.0%)

6 (30.0%)

III

65 (65.0%)

14 (46.7%)

5 (50.0%)

9 (45.0%)

IV

26 (26.0%)

8 (26.7%)

3 (30.0%)

5 (25.0%)

Histology

    

Serous

82 (82.0%)

24 (80.0%)

7 (70.0%)

17 (85.0%)

Mixed

7 (7.0%)

2 (6.6%)

1 (10.0%)

1 (5.0%)

Endometroid

5 (5.0%)

3 (10.0%)

1 (10.0%)

2 (10.0%)

Unclassified

6 (6.0%)

1 (3.3%)

1 (10.0%)

0

Grade of differentiation

    

1

7 (7.0%)

0

0

0

2

26 (26.0%)

5 (16.6%)

1 (10.0%)

4 (20.0%)

3

67 (67.0%)

24 (80.0%)

9 (90.0%)

15 (75.0%)

Unknown

0

1 (3.3%)

0

1 (5.0%)

Survival >5 years

23 (23.0%)

10 (33.3%)

3 (30.0%)

7 (35.0%)

TP53 mutation status

72.0%

53.3%

50.0%

55.0%

All tumors are epithelial adenocarcinomas

Methods

DNA extraction and TP53mutation analysis

DNA was manually extracted from paraffin-embedded tissue sections of tumor material using 5 sections of 10 μ. A modification of the procedure described by Miller [33] was used. The modification included using as much as possible of the top water layer of the 700 ml DNA/lysis buffer and 1 ml phenol/chloroform/water mix, and repeating the extraction step once. The protocol was optimized to give high yield of good quality DNA.

Mutation analyses of exons 2–11 of the TP53 gene in the 30 cases with BRCA1 germ line mutations were performed by TTGE followed by sequencing. Primers, PCR conditions and gel running conditions were as described elsewhere [34]. Samples with aberrantly migrating bands on TTGE were isolated, submitted to a new PCR and sequenced. Analysis of the fresh frozen specimen of tumor DNA from the 100 sporadic cases has previously been reported [29].

Statistical analyses

In univariate analyses, a log rank test have been used to investigate the effect of age at diagnosis, BRCA1 and TP53 mutations on the survival rate. In multivariate analyses, Cox proportional hazards regression analysis was used. Hazard ratios (HR's) are given with 95% confidence intervals (CI's). Statistical significance rates were set at 0.05. The software SAS® version 8.2 was used for statistical analyses.

Results

TP53characterizations and novel mutations

Nineteen of the 30 ovarian carcinomas showed one or more aberrant migrating bands on TTGE in one or more exons and was sequenced (Table 2). A total of 21 sequence changes were detected. Two cases had two different TP53 sequence changes in their tumors, one being a silent mutation. Nine mutations were missense mutations, four nonsense, three were silent sequence changes (not previously reported as polymorphisms) and two were intronic sequence changes of unknown function.
Table 2

TP53 mutations, survival and histopathological features for each case.

Case

a BRCA1 carrier type

Stage

bGrade

Type

TTGE

Exon

Codon

Mutation

aa change

Age of diagnosis

cSurvival months

dVital status

3453

1

3

2

ser

pos

5

 

559+1G>A

splice

53

83

1

10

1

3

3

ser

pos

6

213

CGA>TGA

arg>stop

65

22

3

2857

1

3

3

ser

pos

6

213

CGA>TGA

arg>stop

53

83

3

4

1

4

3

ser

pos

6

216

GTG>ATG

val>met

59

11

3

27

1

2

3

endo

pos

7

237

ATG>ATA

met>ile

39

61

3

8 e

1

3

3

ser

pos

7

260

TCC>TCT

ser>ser

49

84

3

      

8

306

CGA>TGA

arg>stop

   

14

1

1

3

ser

pos

8

267

CGG>CAG

arg>gln

51

25

3

13

1

4

3

ser

pos

8

273

CGT>AGT

arg>ser

39

15

3

29

1

3

3

mix

pos

8

273

CGT>TGT

arg>cys

50

36

3

2842

1 1

4

3

ser

pos

8

273

CGT>TGT

arg>cys

39

35

3

21

1

3

3

ser

pos

8

293

GGG>AGG

gly>arg

39

21

3

26

1

3

2

ser

pos

 

intron

G>A

ivs5

53

93

1

9

1

4

2

ser

neg

    

50

39

3

11

1

3

3

ser

neg

    

44

8

3

17

1

3

3

ser

neg

    

47

30

3

24

1

2

4

ser

neg

    

59

20

3

34

1

1

3

ser

neg

    

46

120

1

30

1

1

2

ser

neg

    

43

199

2

32

1

2

3

ser

neg

    

48

108

1

3351

1

4

3

endo

neg

    

44

9

3

1

2

4

3

ser

pos

5

144

CAG>TAG

gln>stop

41

1

3

3

2

3

3

uncl

pos

6

196

CGA>TGA

arg>stop

48

46

3

20

2

3

3

ser

pos

6

205

TAT>TCT

tyr>ser

52

36

3

28

2

4

3

ser

pos

7

261

AGG>AGA

arg>arg

80

12

3

7 e

2

3

3

ser

pos

7

255

ATC>GTC

ile>val

58

30

3

      

5

141

TGC>TGT

cys>cys

   

12

2

1

3

ser

pos

8

280

AGA>GGA

arg>gly

49

134

1

15

2

3

3

ser

pos

 

intron

C>T

ivs7

50

19

3

5

2

4

3

ser

neg

    

60

45

3

18

2

2

3

endo

neg

    

44

117

3

22

2

3

2

mix

neg

    

47

96

3

a: 1 = 1675delA and 2 = 1135insA. b: undifferentiated (4). c: all patients were followed until diseased or to 15th April, 2004. d: alive without cancer (1), alive with cancer (2), and dead by cancer (3). e: two different mutations detected in sample.

The frequency of transitions vs. transversion in this hereditary cohort (85.7% and 14.3%) was also quite similar to that reported in the IARC database for sporadic cases (88% and 12%), but differed slightly from the sporadic cases in this study (76.4% and 23.6%). The frequency of mutations likely to cause protein alteration were 68.0% (68/100) for the sporadic cases and 53.3%(16/30) for the familial cases. The TP53 mutation frequency in the two different BRCA1 carriers differed slightly with 11/20 (55.0%) in the BRCA1 1675delA carriers and 5/10 (50.0%) in the BRCA1 1135insA carriers. The 1675delA carriers had 7.7% transversions and 92.3% transitions while the 1135insA carriers had 12.5% transversion and 82.5% transitions. Four of the TP53 mutations were novel and not previously reported in ovarian cancer in the IARC TP53 Database [35] or the SOUSSI database. These mutations affected codon 205 (tyr>ser), 260 (ser>ser), 267 (arg>gln) and 293 (gly>arg). All mutations detected resided in exons 5–8. When comparing the TP53 mutation spectrum in these familial cases with that of ovarian cancers cases reported in the IARC database and to the 100 sporadic ovarian cancer cases with a TP53 mutation, no obvious differences were seen either with respect to exon distribution or codon wise (data not shown), although a slightly lower frequency of mutations in exon 5 and a slightly higher in exon 8 were seen in the hereditary cases. The TP53 mutations in the 100 sporadic cases used in this study is reported elsewhere [29].

Age at diagnosis, survival, BRCA1 and TP53status

Median age at diagnosis among sporadic cases and familial cases that carried 1675delA or 1135insA mutations is presented in Table 1. As expected, the familial cases are diagnosed earlier in life than sporadic cases (p < 0.001). The difference in median age of onset between the 1135insA and 1675delA mutation carriers was not significant (p = 0.245).

In the univariate analysis of the combined group, neither BRCA1 status nor age at diagnosis was significantly associated to survival (p = 0.87 and p = 0.50 for BRCA1 status and age at diagnosis (categorized into < 50 and ≥ 50 years), respectively). TP53 mutation did not significantly reduce the survival rates (p = 0.35). Notably, interaction between BRCA1 status and TP53 status was borderline significant (test for interaction: p = 0.06) while the one between BRCA1 status and age at diagnosis was statistically significant (test for interaction: p = 0.05). We further analyzed these factors adjusted for tumor grade, however, results did not substantially change (test interaction: p = 0.04 and p = 0.05 for BRCA1*TP53 and BRCA1*age at diagnosis, respectively).

No association between age at diagnosis and survival time was found among sporadic cases (p = 0.88). Familial cases with late age at diagnosis (≥50 years) had a slightly higher risk of dying than the cases with an early age at diagnosis, however the association did not reach significance, possibly due to a lack of statistical power (RR = 1.65, 95% CI [0.79–3.43], p = 0.14). Among cases diagnosed at age 50 years or more, familial cases had a trend towards a higher risk of dying than sporadic cases (RR = 1.75, 95% CI [0.93–3.30], p = 0.08). After adjustment for the effect of tumor grade and TP53 status (RR = 1.80, 95% CI [0.94–3.43], p = 0.08) (data not shown). Table 3 shows the risk ratios associated to TP53 mutations after stratification for BRCA1 status.
Table 3

Hazard risk of TP53 mutations on familial and sporadic ovarian cancer cases.

 

# cases

HR

CI (95%)

p-value

Familial Cases

30

   

TP53 no mutation

14

1 (ref)

  

TP53 mutation

16

1.64

0.71 – 3.78

0.25

Sporadic cases

100

   

TP53 no mutation

26

1 (ref)

  

TP53 mutation

76

0.96

0.55 – 1.66

0.88

There was no significant difference in survival observed among TP53 mutations carriers compared to non-TP53 mutations carriers, neither for the familial nor the sporadic cases (Log-rank test for TP53 in familial cases: p = 0.25 and log-rank test for TP53 in sporadic cases: p = 0.88) (Table 3).

Discussion

Some studies have reported an enhanced survival for BRCA1 carriers with ovarian cancer compared to sporadic cases [1214, 36, 37], but these studies have not taken TP53 status in the tumors in to consideration. Other studies in which TP53 status have been included concludes that there is no difference in survival [16].

Our results do not show an enhanced survival rate for familial cases compared to sporadic cases, even after adjustment for TP53 status when all age groups were included. Further, no significant difference in survival rates was observed between the familial cases with and without TP53 mutations (Table 3).

These results do not support earlier observations regarding the importance of the p53/BRCA1 interaction on cell proliferation and ovarian carcinogenesis. Most penetrance estimates and survival rates are based on studies in populations with strong founder effects, and may therefore be biased [1517, 38]. Two Ashkenazi founder mutations occur in BRCA1 185delAG and 5382insC (carrier frequencies of 0.9% and 0.13%), with mean age at diagnosis 54 years. How the type of mutation in the BRCA1 gene affects survival, age at diagnosis of the disease, the response to environmental exposure causing DNA damage, and the efficiency of DNA repair, is not clarified. Heterozygote advantage or an increase in biological fitness conferred on carriers of a disease causing mutation (like BRCA1?), often a resistance to certain infections that were common in times past, can cause an increase in allele frequency [39]. Genetic factors with impact on survival and age at onset of disease, to after childbearing age, would be preferential.

The trend for an increased survival in favour of the early age at onset in familial cases compared to late age at onset in familial cases may be attributed to younger patients having greater physical strength, less somatic mutations, and manage illness better than older patients. On the other hand, one might also expect this trend in sporadic cases, which was not the case. One limitation of our study is the small numbers of BRCA1 carriers. In our study, the statistical power to detect BRCA1 effect was 76%.

Consequently, our findings should be confirmed in larger studies. The conflicting literature on the impact of BRCA1 mutation status on ovarian cancer survival should promote additional studies from different ethnic populations, and thereby allow investigators to study whether or not there is a survival benefit due to BRCA1 mutation, or may be secondary to other common inherited genetic factors, which may be shared in ethnic or geographic isolated populations.

Alterations in the TP53 gene have been shown to affect breast cancer survival and in particular patients with mutations in the zinc-binding domains have poor survival [40]. In sporadic ovarian carcinoma several studies reports that no or little effect of TP53 mutations have been seen [17, 24, 28], which is similar to the results reported here. TP53 alterations are also suggested to alter ovarian cancer survival in BRCA1 germ line patients [13, 14], while other groups concludes with a failure of BRCA1 dysfunction to alter ovarian cancer survival [16]. It should also be noted that a considerable fraction (60–80%) of all familial BRCA1 ovarian cancers harbor TP53 mutations [18, 19, 21, 22]. Only a few studies have reported analysis of TP53 mutations in relation to BRCA1 associated ovarian cancer [20, 41]. The present study is the first investigating somatic TP53 mutations in ovarian tumors from carries of two distinct high penetrant BRCA1 germ-line mutations, relating it to survival and age at diagnosis of disease and compares it to sporadic cases. We have previously studied the distribution in age at diagnosis in BRCA1 carriers and non-carriers as a part of a cohort study. Three percent of Norwegian ovarian cancers are caused by BRCA1 1675delA or 1135insA [31, 42], with a distribution similar to that found in this study (Table 1). Further, Bjørge et al. [43] found that 87.0% of Norwegian sporadic ovarian cancers was papillary serous adenocarcinoma, an aggressive histo-prognostic factor.

Eigthy percent of both familial and sporadic ovarian cancer cases in this study were papillary serous adenocarcinoma. Questions need to be addressed concerning the clinical effects of mutations in the BRCA1 gene, why some mutation carriers develop breast cancer, others develop ovarian cancer, and some develop both. We do not know whether the cancers occurring in mutation carriers are significantly different from those occurring in non carriers. The frequency of TP53 mutations in the familial cases altering the protein was 53.3%, which is somewhat higher than other studies of familial BRCA1 ovarian cancer (31–50%) [1822, 24, 25]. Although the number of familial cases in this study is limited, a slightly higher frequency of mutations was found in exon 8 and a lower frequency in exon 5 compared to sporadic cases in the IARC database. The same tendency has been reported by others [20]. However, a non-significant difference in TP53 mutation frequency was observed between the familial and sporadic cases in this study.

Of the novel mutations found in the familial cohort the codon 205 mutation has previously been reported in several other tumors like head and neck SCC as well as breast- and colorectal carcinoma. The amino acid change in codon 255 and 293 are only reported once, in oesophageal SCC and bladder cancer, respectively. The silent codon 260 mutation are reported in two different cancer tissues; lung (SCLC) and colorectal carcinoma. Environmental exposure, both external and internal, is known to influence the spectrum of mutations. Whether hormonal disturbance may affect the mutation rate and spectrum is not known, but if so, it may be expected that BRCA1 carriers are more sensitive to such exposure.

Conclusion

Interestingly, no difference in survival was observed between TP53 mutation carriers among the familial carries or among the sporadic cases (Table 3). Further, we did not find an overall difference in survival between familial BRCA1 carriers and sporadic epithelial ovarian cancer cases, even after adjustment for TP53 status. For cases diagnosed over the age 50 there was a trend toward higher survival for sporadic cases.

List of abbreviations

TTGE: 

temporal temperature gradient gel electrophoresis

PCR: 

polymerase chain reaction

FIGO: 

International Federation of Gynaecology and Obstetrics

RR: 

risk ratio.

Declarations

Acknowledgements

Pedro Kringen is a research fellow of The Norwegian Cancer Society. Guro Elisabeth Lind is acknowledged for working out the optimal condition for DNA extraction from paraffin embedded tissues. We thank Sigrid Lystad and Phuong Vu for providing excellent technical assistance.

This work was supported by grants from The Norwegian Cancer Society and The Norwegian Research Council.

Authors’ Affiliations

(1)
Department of Genetics, The Norwegian Radium Hospital
(2)
Department of Gynecologic Oncology, The Norwegian Radium Hospital
(3)
University of Oslo, The Norwegian Radium Hospital
(4)
Department of Pathology, The Norwegian Radium Hospital
(5)
Institute of Community Medicine, University of Tromsø

References

  1. The Norwegian Cancer Registry: Cancer in Norway 1998. The Cancer Registry of Norway. [http://www.kreftregisteret.no/]
  2. Engeland A, Haldorsen T, Tretli S, Hakulinen T, Horte LG, Luostarinen T, Magnus K, Schou G, Sigvaldason H, Storm HH, et al: Prediction of cancer incidence in the Nordic countries up to the years 2000 and 2010. A collaborative study of the five Nordic Cancer Registries. APMIS Suppl. 1993, 38: 1-124.PubMedGoogle Scholar
  3. Zweemer RP, Verheijen RH, Menko FH, Gille JJ, van Diest PJ, Coebergh JW, Shaw PA, Jacobs IJ, Kenemans P: Differences between hereditary and sporadic ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 1999, 82 (2): 151-153. 10.1016/S0301-2115(98)00218-8.View ArticlePubMedGoogle Scholar
  4. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266 (5182): 66-71.View ArticlePubMedGoogle Scholar
  5. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G: Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995, 378 (6559): 789-792. 10.1038/378789a0.View ArticlePubMedGoogle Scholar
  6. Boyd J: Molecular genetics of hereditary ovarian cancer. Oncology (Huntingt). 1998, 12 (3): 399-406; discussion 409-10, 413.Google Scholar
  7. Lynch HT, Watson P, Lynch JF, Conway TA, Fili M: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer. 1993, 71 (2 Suppl): 573-581.PubMedGoogle Scholar
  8. Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995, 57 (6): 1457-1462.PubMedPubMed CentralGoogle Scholar
  9. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998, 62 (3): 676-689. 10.1086/301749.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Dorum A, Heimdal K, Hovig E, Inganas M, Moller P: Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer. Am J Hum Genet. 1999, 65 (3): 671-679. 10.1086/302530.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Dorum A, Moller P, Kamsteeg EJ, Scheffer H, Burton M, Heimdal KR, Maehle LO, Hovig E, Trope CG, van der Hout AH, van der Meulen MA, Buys CH, te Meerman GJ: A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing. Eur J Cancer. 1997, 33 (14): 2390-2392. 10.1016/S0959-8049(97)00328-6.View ArticlePubMedGoogle Scholar
  12. Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA, LiVolsi VA, Berchuck A, Muto MG, Garber JE, Weber BL, Lynch HT, Boyd J: Clinical and pathological features of ovarian cancer in women with germ- line mutations of BRCA1. N Engl J Med. 1996, 335 (19): 1413-1416. 10.1056/NEJM199611073351901.View ArticlePubMedGoogle Scholar
  13. Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, Ben-Baruch G, Fishman A, Levavi H, Lubin F, Menczer J, Piura B, Struewing JP, Modan B: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol. 2002, 20 (2): 463-466. 10.1200/JCO.20.2.463.View ArticlePubMedGoogle Scholar
  14. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY: Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 2003, 97 (9): 2187-2195. 10.1002/cncr.11310.View ArticlePubMedGoogle Scholar
  15. Johannsson OT, Ranstam J, Borg A, Olsson H: Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol. 1998, 16 (2): 397-404.PubMedGoogle Scholar
  16. Buller RE, Shahin MS, Geisler JP, Zogg M, De Young BR, Davis CS: Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res. 2002, 8 (5): 1196-1202.PubMedGoogle Scholar
  17. Smith-Sorensen B, Kaern J, Holm R, Dorum A, Trope C, Borresen-Dale AL: Therapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to TP53 gene status. Br J Cancer. 1998, 78 (3): 375-381.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Ramus SJ, Bobrow LG, Pharoah PD, Finnigan DS, Fishman A, Altaras M, Harrington PA, Gayther SA, Ponder BA, Friedman LS: Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer. 1999, 25 (2): 91-96. 10.1002/(SICI)1098-2264(199906)25:2<91::AID-GCC3>3.0.CO;2-5.View ArticlePubMedGoogle Scholar
  19. Tworek H, Peng R, Fetzer S, Werness BA, Piver MS, Allen HJ, DiCioccio RA: Mutation analysis of BRCA1, TP53, and KRAS2 in ovarian and related pelvic tumors. Cancer Genet Cytogenet. 1999, 112 (2): 105-118. 10.1016/S0165-4608(98)00267-2.View ArticlePubMedGoogle Scholar
  20. Buller RE, Lallas TA, Shahin MS, Sood AK, Hatterman-Zogg M, Anderson B, Sorosky JI, Kirby PA: The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer. Clin Cancer Res. 2001, 7 (4): 831-838.PubMedGoogle Scholar
  21. Rhei E, Bogomolniy F, Federici MG, Maresco DL, Offit K, Robson ME, Saigo PE, Boyd J: Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. Cancer Res. 1998, 58 (15): 3193-3196.PubMedGoogle Scholar
  22. Schorge JO, Muto MG, Lee SJ, Huang LW, Welch WR, Bell DA, Keung EZ, Berkowitz RS, Mok SC: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res. 2000, 60 (5): 1361-1364.PubMedGoogle Scholar
  23. Wertheim I, Muto MG, Welch WR, Bell DA, Berkowitz RS, Mok SC: p53 gene mutation in human borderline epithelial ovarian tumors. J Natl Cancer Inst. 1994, 86 (20): 1549-1551.View ArticlePubMedGoogle Scholar
  24. Fallows S, Price J, Atkinson RJ, Johnston PG, Hickey I, Russell SE: P53 mutation does not affect prognosis in ovarian epithelial malignancies. J Pathol. 2001, 194 (1): 68-75. 10.1002/path.857.View ArticlePubMedGoogle Scholar
  25. Ozalp S, Yalcin OT, Minsin TH: Expression of p53 in epithelial ovarian cancer. Int J Gynaecol Obstet. 2000, 71 (3): 277-278. 10.1016/S0020-7292(00)00309-X.View ArticlePubMedGoogle Scholar
  26. Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A: Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997, 11 (10): 1226-1241.View ArticlePubMedGoogle Scholar
  27. Sourvinos G, Spandidos DA: Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun. 1998, 245 (1): 75-80. 10.1006/bbrc.1998.8379.View ArticlePubMedGoogle Scholar
  28. Wang Y, Helland A, Holm R, Skomedal H, Abeler VM, Danielsen HE, Trope CG, Borresen-Dale AL, Kristensen GB: TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival. Br J Cancer. 2004, 90 (3): 678-685. 10.1038/sj.bjc.6601537.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Wang Y, Kringen P, Kristensen GB, Holm R, Baekelandt MM, Olivier M, Skomedal H, Hainaut P, Trope CG, Abeler VM, Nesland JM, Borresen-Dale AL, Helland A: Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma. Hum Mutat. 2004, 24 (1): 21-34. 10.1002/humu.20055.View ArticlePubMedGoogle Scholar
  30. Andersen TI, Borresen AL, Moller P: A common BRCA1 mutation in Norwegian breast and ovarian cancer families?. Am J Hum Genet. 1996, 59 (2): 486-487.PubMedPubMed CentralGoogle Scholar
  31. Dorum A, Hovig E, Trope C, Inganas M, Moller P: Three per cent of Norwegian ovarian cancers are caused by BRCA1 1675delA or 1135insA. Eur J Cancer. 1999, 35 (5): 779-781. 10.1016/S0959-8049(99)00050-7.View ArticlePubMedGoogle Scholar
  32. Borg A, Dorum A, Heimdal K, Maehle L, Hovig E, Moller P: BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations. Dis Markers. 1999, 15 (1-3): 79-84.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988, 16 (3): 1215-View ArticlePubMedPubMed CentralGoogle Scholar
  34. Sorlie T, Johnsen H, Vu P, Lind GE, Lothe R, Borresen-Dale AL: Mutation Screening of the TP53 Gene by Temporal Temperature Gradient Gel Electrophoresis. Methods Mol Biol. 2004, 291: 207-216.Google Scholar
  35. Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P: The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002, 19 (6): 607-614. 10.1002/humu.10081.View ArticlePubMedGoogle Scholar
  36. Zweemer RP, Shaw PA, Verheijen RM, Ryan A, Berchuck A, Ponder BA, Risch H, McLaughlin JR, Narod SA, Menko FH, Kenemans P, Jacobs IJ: Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations. J Clin Pathol. 1999, 52 (5): 372-375.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Zweemer RP, Verheijen RH, Coebergh JW, Jacobs IJ, van Diest PJ, Gille JJ, Skates S, Menko FH, Ten Kate LP, Kenemans P: Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol. 2001, 98 (2): 219-223. 10.1016/S0301-2115(01)00318-9.View ArticlePubMedGoogle Scholar
  38. Goldgar DE, Reilly PR: A common BRCA1 mutation in the Ashkenazim. Nat Genet. 1995, 11 (2): 113-114. 10.1038/ng1095-113.View ArticlePubMedGoogle Scholar
  39. Offman J, Opelz G, Doehler B, Cummins D, Halil O, Banner NR, Burke MM, Sullivan D, Macpherson P, Karran P: Defective DNA Mismatch Repair in Acute Myeloid Leukemia/Myelodysplastic Syndrome After Organ Transplantation. Blood. 2004Google Scholar
  40. Borresen AL, Andersen TI, Eyfjord JE, Cornelis RS, Thorlacius S, Borg A, Johansson U, Theillet C, Scherneck S, Hartman S, et al: TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains. Genes Chromosomes Cancer. 1995, 14 (1): 71-75.View ArticlePubMedGoogle Scholar
  41. Buller RE, Sood AK, Lallas T, Buekers T, Skilling JS: Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer [see comments]. J Natl Cancer Inst. 1999, 91 (4): 339-346. 10.1093/jnci/91.4.339.View ArticlePubMedGoogle Scholar
  42. Bjorge T, Engeland A, Sundfor K, CG. T: Prognosis of 2,800 patients with epithelial ovarian cancer diagnosed during 1975-94 and treated at the Norwegian Radium Hospital. Acta Obstet Gynecol Scand. 1998, 77 (7): 777-781. 10.1034/j.1600-0412.1998.770714.x.View ArticlePubMedGoogle Scholar
  43. Bjorge T, Engeland A, Hansen S, Trope CG: Prognosis of patients with ovarian cancer and borderline tumours diagnosed in Norway between 1954 and 1993. Int J Cancer. 1998, 75 (5): 663-670. 10.1002/(SICI)1097-0215(19980302)75:5<663::AID-IJC1>3.0.CO;2-X.View ArticlePubMedGoogle Scholar
  44. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/5/134/prepub

Copyright

© Kringen et al; licensee BioMed Central Ltd. 2005

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.