ABSTRACT
Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCA1 allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1 single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , BRCA1 Protein/genetics , Biomarkers, Tumor/genetics , Germ-Line Mutation , Neoadjuvant Therapy , Neoplasms, Cystic, Mucinous, and Serous/drug therapy , Neoplasms, Cystic, Mucinous, and Serous/genetics , Ovarian Neoplasms/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Cell Proliferation/drug effects , Chemotherapy, Adjuvant , Drug Resistance, Neoplasm/genetics , Female , Genetic Predisposition to Disease , Humans , Loss of Heterozygosity , Neoplasm Recurrence, Local , Neoplasm, Residual , Neoplasms, Cystic, Mucinous, and Serous/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Phenotype , Polymorphism, Single Nucleotide , Treatment Outcome , Tumor Burden/drug effectsABSTRACT
PURPOSE: Adipose tissue products may contribute to endometrial cancer (EC) initiation and further growth that encourages the analysis of this issue in patients with different obesity phenotypes. METHODS/PATIENTS: Omental fat depot characteristics were studied in EC patients (n = 57) with "standard" (SO) or "metabolically healthy" (MHO) obesity. Collected omental samples were evaluated by immunohistochemistry /IHC/ for brown fat marker UCP1, CYP19 (aromatase) and macrophage infiltration markers (CD68, CD163, crown-like structures/CLS) expression. Total RNA extracted from the same samples was investigated for UCP1, CYP19, PTEN and adipokine omentin mRNA. RESULTS: Immunohistochemistry data revealed a statistically significant increase in aromatase and CD68 expression and tendency to increase of UCP1 expression in SO patients' omental fat compared to samples obtained from MHO patients. Additionally, positive correlation of EC clinical stage with UCP1 protein and its mRNA content in omental fat was pronounced in MHO as well as SO group, while with omentin mRNA it was discovered only in patients with SO. An inclination to the correlation with better tumor differentiation was seen for UCP1 and CD68 protein expression in patients with MHO and with worse (high grade) differentiation-for CD68 expression in the group with SO. CONCLUSIONS: In aggregate, this suggests that obesity phenotype has significant impact on omental fat tissue characteristics which is related to the clinical course of EC and may have practical consequences.
