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Patterns of loss of heterozygosity in breast carcinoma during neoadjuvant chemotherapy
Claire Oudin1, Frank Bonnetain, Romain Boidot
1Laboratory of Molecular Genetics, Centre Georges François Leclerc, INSERM U-517, Dijon, France.
Abstract:
There is evidence indicating that resistance to some chemotherapy drugs is related to enhanced repair of DNA lesions. Microsatellite instability (MSI) and loss of heterozy-gosity (LOH) reflect genetic instability and are associated with specific DNA repair pathways. Despite the strong implication of genetic instability in breast cancer its association with chemotherapy is unknown. Thus, we analyzed microsatellite alterations with 12 markers in locally advanced breast carcinomas in relation to neoadjuvant epirubicin-cyclophosphamide-containing chemotherapy (FEC-100) and compared it to a docetaxol-based (Tax-Epi) regimen. Samples were obtained before, during and after treatments. In pre-treated samples, MSI was detected only in 2 cases (7%) whereas LOH was found in 23 of the 34 (68%) carcinomas including 10 belonging to the FEC-100 group and 13 to Tax-Epi one. LOH frequency decreased from the first course of both regimens, but differences between the patterns of LOH during treatment were found. Persistent LOH was more frequent in FEC-100 group (71% vs. 41%) that was detected only in biopsies belonging to non-responder patients. Persistent LOH were clustered at particular loci located at regions containing common fragile sites (FHIT and FRA6E). Analysis of baseline LOH with 6 markers located at 3p indicates discontinuous patterns reflecting double-strand break (DSB) lesions. These results agree with a drug-dependent link between genetic instability and chemoresistance and show that FEC-100 treatment is associated with DSB accumulation manifested as LOH in tumor cells resistant to chemotherapy in breast carcinoma.
Insights
Genetic instability, specifically loss of heterozygosity (LOH), is linked to chemotherapy resistance in breast cancer. FEC-100 treatment showed increased LOH in non-responders, suggesting a drug-dependent chemoresistance mechanism.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Chemotherapy resistance in breast cancer is a significant clinical challenge.
- Enhanced DNA repair mechanisms are implicated in drug resistance.
- Genetic instability, including microsatellite instability (MSI) and loss of heterozygosity (LOH), is linked to DNA repair pathways but its role in breast cancer chemotherapy is unclear.
Purpose of the Study:
- To investigate the association between genetic instability, specifically microsatellite alterations (MSI and LOH), and response to neoadjuvant chemotherapy in locally advanced breast carcinomas.
- To compare the patterns of genetic instability during treatment with epirubicin-cyclophosphamide (FEC-100) versus docetaxel-based (Tax-Epi) regimens.
- To determine if LOH accumulation correlates with chemoresistance and specific DNA damage in breast cancer.
Main Methods:
- Analysis of microsatellite alterations using 12 markers in 34 locally advanced breast carcinomas before, during, and after neoadjuvant chemotherapy.
- Comparison of LOH and MSI frequencies between FEC-100 and Tax-Epi treatment groups.
- Correlation of LOH patterns with patient response to chemotherapy and identification of specific genomic loci affected.
Main Results:
- Loss of heterozygosity (LOH) was detected in 68% of pre-treated breast carcinomas, while microsatellite instability (MSI) was rare (7%).
- LOH frequency decreased during chemotherapy, but persistent LOH was more common in the FEC-100 group (71% vs. 41%) and was associated with non-response to treatment.
- Persistent LOH in FEC-100 non-responders was clustered at common fragile sites (FHIT, FRA6E), and baseline LOH patterns suggested double-strand break (DSB) accumulation.
Conclusions:
- Chemotherapy resistance in breast cancer is associated with drug-dependent genetic instability.
- The FEC-100 regimen is linked to the accumulation of double-strand breaks, manifesting as LOH in chemoresistant tumor cells.
- LOH analysis can serve as a biomarker for predicting chemotherapy response and understanding resistance mechanisms in breast cancer.
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