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Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas.

Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, Welcsh P - Mol. Cancer (2009)

Bottom Line: BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards).In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%).Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA. swishere@u.washington.edu

ABSTRACT

Background: DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.

Results: Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms.

Conclusion: Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.

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Overall survival in relation to BRCA1 expression in primary sporadic ovarian carcinomas. Overall survival was significantly improved in primary ovarian carcinomas (p = 0.02, LogRank test) with low BRCA1 protein expression (median survival 62 months) compared to carcinomas with intermediate or normal BRCA1 expresssion (median survival 45 months).
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Figure 4: Overall survival in relation to BRCA1 expression in primary sporadic ovarian carcinomas. Overall survival was significantly improved in primary ovarian carcinomas (p = 0.02, LogRank test) with low BRCA1 protein expression (median survival 62 months) compared to carcinomas with intermediate or normal BRCA1 expresssion (median survival 45 months).

Mentions: Individual factors influencing survival in this cohort in univariate analyses were stage (p = 0.01), age (p = 0.03) and optimal cytoreduction to a maximum neoplastic diameter less than 1 cm (p < 0.0001) and low BRCA1 expression (p = 0.02). Low BRCA1 expression in the primary carcinoma was associated with longer survival compared to intermediate or normal BRCA1 expression (median survival 62 months vs. 45 months, p = 0.02 LogRank Test, Hazard Ratio 0.59, 95% confidence interval 0.37–0.93, Figure 4). Low BRCA1 expression remained significantly associated with improved survival in a Cox multi regression model with the covariates age (p = 0.04) or stage (p = 0.04) but was no longer significant when using the co-variate optimal cytoreduction (p = 0.10). Individual factors not related to survival included grade, MLH1 or BRCA2 protein expression, methylation of BRCA1, MLH1 or FANCF genes, or p53 mutation.


Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas.

Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, Welcsh P - Mol. Cancer (2009)

Overall survival in relation to BRCA1 expression in primary sporadic ovarian carcinomas. Overall survival was significantly improved in primary ovarian carcinomas (p = 0.02, LogRank test) with low BRCA1 protein expression (median survival 62 months) compared to carcinomas with intermediate or normal BRCA1 expresssion (median survival 45 months).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719582&req=5

Figure 4: Overall survival in relation to BRCA1 expression in primary sporadic ovarian carcinomas. Overall survival was significantly improved in primary ovarian carcinomas (p = 0.02, LogRank test) with low BRCA1 protein expression (median survival 62 months) compared to carcinomas with intermediate or normal BRCA1 expresssion (median survival 45 months).
Mentions: Individual factors influencing survival in this cohort in univariate analyses were stage (p = 0.01), age (p = 0.03) and optimal cytoreduction to a maximum neoplastic diameter less than 1 cm (p < 0.0001) and low BRCA1 expression (p = 0.02). Low BRCA1 expression in the primary carcinoma was associated with longer survival compared to intermediate or normal BRCA1 expression (median survival 62 months vs. 45 months, p = 0.02 LogRank Test, Hazard Ratio 0.59, 95% confidence interval 0.37–0.93, Figure 4). Low BRCA1 expression remained significantly associated with improved survival in a Cox multi regression model with the covariates age (p = 0.04) or stage (p = 0.04) but was no longer significant when using the co-variate optimal cytoreduction (p = 0.10). Individual factors not related to survival included grade, MLH1 or BRCA2 protein expression, methylation of BRCA1, MLH1 or FANCF genes, or p53 mutation.

Bottom Line: BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards).In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%).Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA. swishere@u.washington.edu

ABSTRACT

Background: DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.

Results: Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms.

Conclusion: Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.

Show MeSH
Related in: MedlinePlus