Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca2+ traffic and response to neoadjuvant chemotherapy.

Overexpression of Bcl-2 proteins such as Bcl2L10, also referred to as Nrh, is associated with resistance to therapy and poor survival in various cancers, including breast cancer, lung cancer, and leukemia. The single nucleotide polymorphism (SNP) of BCL2L10 in its BH4 domain at position 11 (BCL2L10 Leu11Arg, rs2231292), corresponding to position 11 in the Nrh open reading frame, is reported to lower resistance towards chemotherapy, with patients showing better survival in the context of acute leukemia and colorectal cancer. Using cellular models and clinical data, we aimed to extend this knowledge to breast cancer. We report that the homozygous status of the Nrh Leu11Arg isoform (Nrh-R) is found in 9.7-11% percent of the clinical datasets studied. Furthermore, Nrh-R confers higher sensitivity towards Thapsigargin-induced cell death compared to the Nrh-L isoform, due to altered interactions with IP3R1 Ca2+ channels in the former case. Collectively, our data show that cells expressing the Nrh-R isoform are more prone to death triggered by Ca2+ stress inducers, compared to Nrh-L expressing cells. Analysis of breast cancer cohorts revealed that patients genotyped as Nrh-R/Nrh-R may have a better outcome. Overall, this study supports the notion that the rs2231292 Nrh SNP could be used as a predictive tool regarding chemoresistance, improving therapeutic decision-making processes. Moreover, it sheds new light on the contribution of the BH4 domain to the anti-apoptotic function of Nrh and identifies the IP3R1/Nrh complex as a potential therapeutic target in the context of breast cancer.

Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10.

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain-dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404-17. ©2018 AACR.

DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study.

AIMS: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli-Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs). METHODS AND RESULTS: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J-GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1-mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours. CONCLUSIONS: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options.

Large-scale investigation of base excision repair genetic polymorphisms and lung cancer risk in a multicenter study.

BACKGROUND: Base excision repair (BER) is a highly conserved essential mechanism for maintaining genome integrity. We examined associations among four well-characterized polymorphisms of BER genes (OGG1 Ser326Cys, XRCC1 Arg194Trp, XRCC1 Arg280His, and XRCC1 Arg399Gln) and lung cancer risk. METHODS: A total of 2188 patients with lung cancer and 2198 control subjects without lung cancer recruited at 15 centers in six Eastern European countries from February 1998 to October 2002 provided DNA samples for genotype analysis. Genetic polymorphisms were analyzed by the fluorescence 5' exonuclease and Amplifluor assays. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We estimated the false-positive reporting probability (FPRP) for our results by incorporating a range of prior probabilities that specific polymorphisms are associated with lung cancer risk. All statistical tests were two-sided. RESULTS: The overall odds ratio for lung cancer among those with the OGG1 Cys/Cys genotype compared with those with the OGG1 Ser/Ser genotype was 1.34 (95% CI = 0.95 to 1.88); the association was most prominent for adenocarcinoma risk (OR = 1.66, 95% CI = 1.04 to 2.66). Overall, the XRCC1 polymorphisms were not associated with the risk of lung cancer. However, the XRCC1 Arg194Trp and Arg280His variants were each associated with a reduced risk of lung cancer among subjects in the highest quartile of pack-years of smoking compared with common allele homozygotes (ORs of 0.65 [95% CI = 0.46 to 0.93] and 0.56 [95% CI = 0.36 to 0.86], respectively). The associations between the OGG1 Cys/Cys genotype and adenocarcinoma risk and between XRCC1 Arg194Trp polymorphism and lung cancer risk among heavy smokers remained robust given prior probabilities of 25% (FPRP = 0.238) and 10% (FPRP = 0.276), respectively. CONCLUSIONS: Our results do not support a major independent role of BER gene polymorphisms in lung cancer risk. However, we cannot exclude the possibility that the OGG1 Ser326Cys and XRCC1 Arg194Trp polymorphisms play minor roles in lung carcinogenesis.

Exon 5 polymorphisms in the O6-alkylguanine DNA alkyltransferase gene and lung cancer risk in non-smokers exposed to second-hand smoke.

PURPOSE: The objective of the study was to examine the association of three exon 5 variants in the O(6)-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O(6)-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers. EXPERIMENTAL DESIGN: Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly(160)Arg, Ile(143)Val, and Lys(178)Arg variant alleles. RESULTS: No codon (160)Arg variant alleles were found in the study population. The codon (143)Val and (178)Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03-4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21-5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91-25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27-4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53-1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes. CONCLUSIONS: These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.