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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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Representative protein expression of BRCA1, BRCA2 and MLH1 in sporadic ovarian carcinomas. Protein expression is represented by brown stain. Black bars in the lower left corners represent 10 microns. A. BRCA1 protein in a neoplasm with low expression. B. BRCA1 protein in a neoplasm with normal expression. C. BRCA2 protein in a neoplasm with low expression. D. BRCA2 protein in a neoplasm with normal expression. E. MLH1 protein in a neoplasm with low expression. F. MLH1 protein in a neoplasm with normal expression.
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Figure 1: Representative protein expression of BRCA1, BRCA2 and MLH1 in sporadic ovarian carcinomas. Protein expression is represented by brown stain. Black bars in the lower left corners represent 10 microns. A. BRCA1 protein in a neoplasm with low expression. B. BRCA1 protein in a neoplasm with normal expression. C. BRCA2 protein in a neoplasm with low expression. D. BRCA2 protein in a neoplasm with normal expression. E. MLH1 protein in a neoplasm with low expression. F. MLH1 protein in a neoplasm with normal expression.

Mentions: BRCA1, BRCA2, and MLH1 protein expression is summarized in Table 2 and representative staining is shown in Figure 1. BRCA1 and BRCA2 protein levels were significantly and positively correlated (p < 0.0001, two-tailed). BRCA1 and BRCA2 protein expression were not related to MLH1 protein expression.


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)

Representative protein expression of BRCA1, BRCA2 and MLH1 in sporadic ovarian carcinomas. Protein expression is represented by brown stain. Black bars in the lower left corners represent 10 microns. A. BRCA1 protein in a neoplasm with low expression. B. BRCA1 protein in a neoplasm with normal expression. C. BRCA2 protein in a neoplasm with low expression. D. BRCA2 protein in a neoplasm with normal expression. E. MLH1 protein in a neoplasm with low expression. F. MLH1 protein in a neoplasm with normal expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Representative protein expression of BRCA1, BRCA2 and MLH1 in sporadic ovarian carcinomas. Protein expression is represented by brown stain. Black bars in the lower left corners represent 10 microns. A. BRCA1 protein in a neoplasm with low expression. B. BRCA1 protein in a neoplasm with normal expression. C. BRCA2 protein in a neoplasm with low expression. D. BRCA2 protein in a neoplasm with normal expression. E. MLH1 protein in a neoplasm with low expression. F. MLH1 protein in a neoplasm with normal expression.
Mentions: BRCA1, BRCA2, and MLH1 protein expression is summarized in Table 2 and representative staining is shown in Figure 1. BRCA1 and BRCA2 protein levels were significantly and positively correlated (p < 0.0001, two-tailed). BRCA1 and BRCA2 protein expression were not related to MLH1 protein expression.

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