Pharmacogenomic predictor of long-term residual chemotherapy-induced peripheral neuropathy in ovarian cancer survivors: A substudy of the GINECO Vivrovaire study.

BACKGROUND: Chemotherapy (CT) remains a backbone treatment of epithelial ovarian cancer (EOC) inducing persistent peripheral neuropathy (CIPN). Using a dedicated patient-reported outcome tool, this study investigated persistent CIPN and its pharmacogenetic predictors in a cohort of long-term EOC survivors. METHODS: Vivrovaire was a French multicenter cohort of patients with EOC free of disease 3 years after CT completion. Persistent CIPN was assessed using the FACT/GOG-Ntx4 self-questionnaire. The association of homozygous (hom) or heterozygous (het) single nucleotide polymorphisms (SNPs) in selected genes was evaluated. RESULTS: 130 patients were included with a median time from CT completion of 63 [35-180] months. The median CIPN score was 37 [18-44], with 35 (26.9%) patients reporting severe CIPN (<33). SNPs were identified as follows: CYP2C8 [hom, n = 32 (24.6%)/het, n = 99, (76.2%)]; CYP3A4 [hom, n = 0 (0%)/het, n = 8 (6.2%)], ERCC1 [hom, n = 21 (16.2%)/het, n = 57 (43.8%)], and XPC [hom, n = 45 (34.6%)/het, n = 66 (50.8%)]. In univariate analysis, the identification of ≥1 hom SNP was associated with a lower CIPN score (continuous variable; p = 0.045). Patients harboring hom or het CYP2C8_rs1934951 SNP reported more likely severe CIPN (threshold <33) score (OR 2.482; 95% CI [1.126-5.47], p = 0.024). In the multivariate analyses, age, interval from CT completion, type and number of CT courses were not significantly associated with CIPN score (OR 5.165, 95% CI [0.478-55.83], p = 0.176). CONCLUSIONS: Persistent CIPN is common among ovarian cancer long-term survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in EOC survivors. More studies are warranted to identify predictive factors of CIPN.

[Biological diagnosis of resistance to erlotinib in a malignant pleural effusion]. / Diagnostic biologique de résistance à l'erlotinib sur une pleurésie.

INTRODUCTION: The characterization of genetic abnormalities in non-small cell lung cancer (NSCLC) constitutes a theranostic revolution which is leading to rapid progress in the personalized management of this condition. CASE REPORT: We present the case of a patient with NSCLC harboring an activating mutation of the Epidermal Growth Factor Receptor (EGFR). After two years of treatment with a tyrosine kinase inhibitor (TKI), the development of a pleural effusion demonstrated that the NSCLC had progressed. The T790M mutation was identified in tumour cells from the pleural aspirate. This anomaly had not been observed in the initial lung biopsy sample. CONCLUSION: The genetic study of tumour cells contained in a biological fluid could be used to initiate molecular monitoring of the NSCLC tumour, without requiring repeated tissue biopsies and to customize the treatment in some patients with NSCLC.

Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma.

OBJECTIVES: Life-threatening toxic side-effects following 5-FU exposure have been related to deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in its catabolism. We presently report a new DPYD gene SNP in a Spanish woman who died from multivisceral 5-FU-induced toxicity. DESIGN AND METHODS: We looked for 22 known SNPs by Pyrosequecing. Then, we sequenced the whole 23 exons of DPYD, along with adjacent intronic sequences. PCR was carried out to determine whether or not exons were deleted in the DPYD. To determine whether the predicted stop codon indeed resulted in a truncated protein, a bacterial expression vector was employed to generate the predicted protein. 500 patients were genotyped to determine allele frequency. RESULTS: A novel mutation 464 T>A was identified in DPYD gene exon 5, resulting in the replacement of leucine 155 by a stop codon in the protein. We confirmed this mutation by Pyrosequencing and its involvement by a protein truncation test. We genotyped the patient's family and the allele frequency was 0.2%. CONCLUSION: The involvement of this variant in 5-FU life-threatening toxicity supports its inclusion in pretherapeutic genetic screening.

Transcriptional suppression of the human T-cell leukemia virus type I long terminal repeat occurs by an unconventional interaction of a CREB factor with the R region.

To analyze regulation of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR), cell lines were generated from LTR-tax x LTR-beta-galactosidase (beta-Gal) doubly transgenic mouse fibroblastic tumors. The HTLV-I LTR directs expression of both the tax and lacZ genes, and Tax up-modulates both promoters in primary cells. However, once cells were transformed by tax, beta-Gal but not tax expression was suppressed. Supertransformation of these cells with v-src suppressed both beta-Gal and tax expression. This suppression was reversed by treatment with the tyrosine kinase inhibitor herbimycin A or protein kinase A inhibitor H8. Electrophoretic mobility shift assays demonstrated augmented binding in the R but not U3 region. This binding was competitively inhibited by a high-affinity CREB oligodeoxynucleotide and super-shifted with a specific CREB antibody. Treatment of cells with the cyclic AMP analog dibutyryl cyclic AMP also transiently increased the R region binding dramatically. In vitro DNase I footprint analysis identified a protein-binding sequence in the R region which corresponded with suppression. However, this target sequence lacked a conventional CREB-binding site. A 70.5-kDa DNA-binding protein was partially purified by affinity chromatography, along with a 49-kDa protein which reacted with CREB-specific sera. These data demonstrate that HTLV-I LTR suppression is associated with CREB factor binding in the R region, probably by direct interaction with a 70.5-kDa protein, and provide a novel mechanism for maintenance of viral latency.