Copy number variation profile in noninvasive prenatal testing (NIPT) can identify co-existing maternal malignancies: Case reports and a literature review.

OBJECTIVE: The coexistence of maternal malignancy and pregnancy has received increasing attention in Noninvasive prenatal testing (NIPT) studies. Malignancy in pregnant women potentially affects the copy number variation (CNV) profile in NIPT results. Only one case of hematologic cancer has been reported in a Hong-Kong pregnant women, and solid tumors have never been reported in pregnant Chinese women. CASE REPORT: The patients with dysgerminoma and cervical cancer showed aberrant chromosomal aneuploidies in NIPT and concordant patterns of genome disruption in tumor tissues. The genomic aberrations in the gastric cancer patient had similar copy number variation pattern of gastric cancer. CONCLUSION: The findings in this study and the literature review further validate the effect of maternal malignancy on the copy number variation profile in NIPT data and strengthen the possibility of detecting malignant tumors with NIPT in the future.

Functional elements in initiation factors 1, 1A, and 2ß discriminate against poor AUG context and non-AUG start codons.

Yeast eIF1 inhibits initiation at non-AUG triplets, but it was unknown whether it also discriminates against AUGs in suboptimal context. As in other eukaryotes, the yeast gene encoding eIF1 (SUI1) contains an AUG in poor context, which could underlie translational autoregulation. Previously, eIF1 mutations were identified that increase initiation at UUG codons (Sui(-) phenotype), and we obtained mutations with the opposite phenotype of suppressing UUG initiation (Ssu(-) phenotype). Remarkably, Sui(-) mutations in eukaryotic translation initiation factor 1 (eIF1), eIF1A, and eIF2ß all increase SUI1 expression in a manner diminished by introducing the optimal context at the SUI1 AUG, whereas Ssu(-) mutations in eIF1 and eIF1A decrease SUI1 expression with the native, but not optimal, context present. Therefore, discrimination against weak context depends on specific residues in eIFs 1, 1A, and 2ß that also impede selection of non-AUGs, suggesting that context nucleotides and AUG act coordinately to stabilize the preinitiation complex. Although eIF1 autoregulates by discriminating against poor context in yeast and mammals, this mechanism does not prevent eIF1 overproduction in yeast, accounting for the hyperaccuracy phenotype afforded by SUI1 overexpression.

Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer.

BACKGROUND: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. METHODOLOGY/PRINCIPAL FINDINGS: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. CONCLUSIONS/SIGNIFICANCE: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models.

eIF1 controls multiple steps in start codon recognition during eukaryotic translation initiation.

Eukaryotic translation initiation factor (eIF) 1 is a central mediator of start codon recognition. Dissociation of eIF1 from the preinitiation complex (PIC) allows release of phosphate from the G-protein factor eIF2, triggering downstream events in initiation. Mutations that weaken binding of eIF1 to the PIC decrease the fidelity of start codon recognition (Sui(-) phenotype) by allowing increased eIF1 release at non-AUG codons. Consistent with this, overexpression of these mutant proteins suppresses their Sui(-) phenotypes. Here, we have examined mutations at the penultimate residue of eIF1, G107, that produce Sui(-) phenotypes without increasing the rate of eIF1 release. We provide evidence that, in addition to its role in gating phosphate release, dissociation of eIF1 triggers conversion from an open, scanning-competent state of the PIC to a stable, closed one. We also show that eIF5 antagonizes binding of eIF1 to the complex and that key interactions of eIF1 with its partners are modulated by the charge at and around G107. Our data indicate that eIF1 plays multiple roles in start codon recognition and suggest that prior to AUG recognition it prevents eIF5 from binding to a key site in the PIC required for triggering downstream events.

Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo.

Selection of the AUG start codon is a key step in translation initiation requiring hydrolysis of GTP in the eIF2*GTP*Met-tRNA(i)(Met) ternary complex (TC) and subsequent P(i) release from eIF2*GDP*P(i). It is thought that eIF1 prevents recognition of non-AUGs by promoting scanning and blocking P(i) release at non-AUG codons. We show that Sui(-) mutations in Saccharomyces cerevisiae eIF1, which increase initiation at UUG codons, reduce interaction of eIF1 with 40S subunits in vitro and in vivo, and both defects are diminished in cells by overexpressing the mutant proteins. Remarkably, Sui(-) mutation ISQLG(93-97)ASQAA (abbreviated 93-97) accelerates eIF1 dissociation and P(i) release from reconstituted preinitiation complexes (PICs), whereas a hyperaccuracy mutation in eIF1A (that suppresses Sui(-) mutations) decreases the eIF1 off-rate. These findings demonstrate that eIF1 dissociation is a critical step in start codon selection, which is modulated by eIF1A. We also describe Gcd(-) mutations in eIF1 that impair TC loading on 40S subunits or destabilize the multifactor complex containing eIF1, eIF3, eIF5, and TC, showing that eIF1 promotes PIC assembly in vivo beyond its important functions in AUG selection.