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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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Schematic of BRCA1, BRCA2, and MLH1 protein expression in paired primary and recurrent neoplasms. Each neoplasm is represented by a single horizontal line. A. BRCA1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy, 8 with second recurrences. B. BRCA1 expression in 7 primary and paired recurrent neoplasms in which the recurrence was obtained more than 6 months since last chemotherapy. C. BRCA2 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. D. BRCA2 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy. E. MLH1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. F. MLH1 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy.
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Figure 2: Schematic of BRCA1, BRCA2, and MLH1 protein expression in paired primary and recurrent neoplasms. Each neoplasm is represented by a single horizontal line. A. BRCA1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy, 8 with second recurrences. B. BRCA1 expression in 7 primary and paired recurrent neoplasms in which the recurrence was obtained more than 6 months since last chemotherapy. C. BRCA2 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. D. BRCA2 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy. E. MLH1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. F. MLH1 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy.

Mentions: MLH1, BRCA1, and BRCA2 protein expression was also assessed in 31 matched primary and recurrent ovarian carcinomas from the same patient to determine if chemotherapy influenced MLH1, BRCA1, or BRCA2 protein levels. In 7 cases a second recurrence was available for expression analyses. For second recurrences, data was tabulated as if for a separate case when compared to the primary. Recurrent neoplasms were obtained at varying time intervals from last chemotherapy. We separated matched pairs into two groups depending on the interval since last chemotherapy exposure (≤ six months or >six months). Complete data for protein and methylation analyses for each case is presented in Table S1; Additional file 1. Changes in protein expression in paired neoplasms are shown schematically in Figure 2 and representative staining in Figure 3.


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)

Schematic of BRCA1, BRCA2, and MLH1 protein expression in paired primary and recurrent neoplasms. Each neoplasm is represented by a single horizontal line. A. BRCA1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy, 8 with second recurrences. B. BRCA1 expression in 7 primary and paired recurrent neoplasms in which the recurrence was obtained more than 6 months since last chemotherapy. C. BRCA2 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. D. BRCA2 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy. E. MLH1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. F. MLH1 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Schematic of BRCA1, BRCA2, and MLH1 protein expression in paired primary and recurrent neoplasms. Each neoplasm is represented by a single horizontal line. A. BRCA1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy, 8 with second recurrences. B. BRCA1 expression in 7 primary and paired recurrent neoplasms in which the recurrence was obtained more than 6 months since last chemotherapy. C. BRCA2 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. D. BRCA2 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy. E. MLH1 protein expression in 24 primary and paired recurrent neoplasms obtained ≤ 6 months since last chemotherapy. F. MLH1 expression in 7 primary and paired recurrent neoplasm obtained more than 6 months since last chemotherapy.
Mentions: MLH1, BRCA1, and BRCA2 protein expression was also assessed in 31 matched primary and recurrent ovarian carcinomas from the same patient to determine if chemotherapy influenced MLH1, BRCA1, or BRCA2 protein levels. In 7 cases a second recurrence was available for expression analyses. For second recurrences, data was tabulated as if for a separate case when compared to the primary. Recurrent neoplasms were obtained at varying time intervals from last chemotherapy. We separated matched pairs into two groups depending on the interval since last chemotherapy exposure (≤ six months or >six months). Complete data for protein and methylation analyses for each case is presented in Table S1; Additional file 1. Changes in protein expression in paired neoplasms are shown schematically in Figure 2 and representative staining in Figure 3.

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