High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

Abstract

BackgroundThe aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment.MethodsA comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4–5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins.ResultsA total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established.ConclusionOur results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

Association of Intron Microsatellite Instability and Exon Mutational Profile of TP53 in Human Gastric Cancers

“…The microsatellite TP53ALU was initially found to be a polymorphism locus that had been frequently used as a marker in previous studies (10,11). Consistently, we observed 9 genotypes of TP53ALU in normal tissues and confirmed that TP53ALU is a highly polymorphic pentanucleotide repeat microsatellite.…”

Characterization of Salt-Induced Epigenetic Segregation by Genome-Wide Loss of Heterozygosity and its Association with Salt Tolerance in Rice (Oryza sativa L.)

“…In humans, a strong correlation was found between LOH events and deficient protein expression of specific genes and the incidence of secondary tumors of breast cancer (Kamat et al, 2012). LOH/LOA on specific chromosomal regions was reported to contribute to the molecular pathway of glioma progression in Malay population (Zainuddin et al, 2004).…”

Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients

“…The importance of studying these instabilities is emphasized by the role MSI and LOH play in the early stages of tumorigenesis and cancer development [ 22 - 24 ]. The assessment of MSI and LOH may carry a predictive value for earlier detection and management of secondary tumors [ 37 , 41 ]. Since previous reports indicate that the use of 10 markers is optimal, the present study used a panel of five microsatellites recommended by the NCI guidelines and another five markers of our choosing [ 42 - 44 ].…”

“…Treatment-related MSI and LOH have been analyzed in a few studies in recent years, highlighting the importance of screening patients for these genomic instabilities after chemotherapy completion [ 35 - 37 ]. Consequences of MSI and LOH that were observed in these studies included increased resistance to chemotherapy, recurrence of primary tumors, and/or appearance of secondary malignancies.…”

“…Following the results reported in our previous study on breast cancer patients [ 37 ], a new study was similarly designed to assess whether patients with other solid tumors are predisposed to higher genetic instability linked to chemotherapy treatment. In addition, the present study includes an extended follow-up period of 52 months to verify if it is possible to correlate MSI, LOH, and reduced MMR expression with clinical findings.…”