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. 2009 Jul 14:8:48.
doi: 10.1186/1476-4598-8-48.

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

Elizabeth M Swisher  1 , Rachel M Gonzalez, Toshiyasu Taniguchi, Rochelle L Garcia, Tom Walsh, Barbara A Goff, Piri Welcsh
Affiliations

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

Elizabeth M Swisher et al. Mol Cancer. .

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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Figures

Figure 1
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.
Figure 2
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.
Figure 3
Figure 3
BRCA1, BRCA2, and MLH1 protein expression in paired primary and recurrent neoplasms. Protein expression is represented by brown stain. Black bars in the lower left corners are equal to 10 microns. A. BRCA1 expression is low in the primary neoplasm. B. BRCA1 expression is increased in the paired recurrent neoplasm. C. BRCA2 protein expression is low in a different primary neoplasm. D. BRCA2 expression is increased in the paired recurrent neoplasm. E. MLH1 protein is normal in a different primary neoplasm. F. In the paired recurrent neoplasm, MLH1 protein expression is reduced.
Figure 4
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).
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