Liying Zhang

Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family

AbstractBackgroundGermline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.MethodsThe proband was tested via a clinical testing, Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). RT‐PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.ResultsWe report a 56‐year‐old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.ConclusionOur results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.

The RAD51D c.82G>A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer

Mutations in RAD51D are associated with a predisposition to primary ovarian, fallopian tube, and peritoneal carcinoma. Our study aims to characterize a RAD51D missense variant in a hereditary ovarian cancer family. The effects of the RAD51D c.82G>A (p.Val28Met) variant on mRNA splicing were evaluated and characterized using RT-PCR, cloning and DNA sequencing. This variant completely disrupts normal splicing and results in the loss of 3'end of 5'UTR and the entire exon 1 (c.-86_c.82), which presumably leads to loss of the RAD51D protein. The RAD51D c.82G>A (p.Val28Met) variant is clinically significant and classified as likely pathogenic. Our results indicate that the RAD51D c.82G>A (p.Val28Met) variant contributes to cancer predisposition through disruption of normal mRNA splicing. The identification of this variant in an individual affected with high-grade serous fallopian tube cancer suggests that the RAD51D variant may contribute to predisposition to the ovarian cancer in this family.

Identification and construction of a prognostic risk model based on multi‐RNA methylation regulators in cervical cancer

AbstractAimCervical cancer is one of the most aggressive female cancers. RNA methylation is a necessary epigenetic modification in biological process. This study aimed to construct an RNA methylation regulator‐based risk model for predicting the prognosis of cervical cancer patients.MethodsThe transcriptome profiles of cervical cancer data were obtained from The Cancer Genome Atlas (TCGA) and GSE44001. An RNA methylation‐related risk model was constructed and assessed by the Least absolute shrinkage and selection operator (Lasso)‐penalized Cox regression model and receiver operating characteristic (ROC). Kaplan–Meier and Cox regression analyses were used to evaluate the prognostic effect of the risk model and calculated scores. The immune infiltration difference was further analyzed between the subgroups with a single‐sample gene set enrichment analysis (ssGSEA).ResultsA total of 63 methylation modulators were included in this study, and 618 cervical cancer patients were identified from TCGA and GSE44001. Differential expression genes profiling RNA methylation regulators between normal and tumor samples were distinct. A four‐gene signature panel was constructed to predict the prognostic risk. The predictive ability was satisfactory. Cervical cancer patients were classified into high‐ or low‐risk subgroups according to the median risk score. Moreover, the immune infiltration patterns between them differed.ConclusionsA risk model including four RNA methylation regulators was constructed, which will provide new perspectives for further investigation of the relationship between RNA methylation and cervical cancer.

Phase II study of the efficacy and safety of palbociclib in patients with recurrent ovarian cancer

We describe a phase II clinical trial evaluating the safety and efficacy of the oral CDK4/6 inhibitor palbociclib in patients with recurrent ovarian cancer. Eligible patients with Response Evaluation Criteria in Solid Tumors (RECIST) and/or CA-125 measurable recurrent ovarian cancer were treated with oral palbociclib 125 mg daily for 21 days of a 28-day cycle. Patients with hormone receptor-positive tumors were allowed to concurrently receive an aromatase inhibitor. The primary endpoint was the biochemical response rate, determined by CA-125 response based on Gynecologic Cancer InterGroup criteria. Genomic analyses were performed using targeted next-generation sequencing. The biochemical response rate among 40 patients was 8.3% (95% CI 2.2 to 23.6), and the objective response rate by CA-125 criteria and/or RECIST was 10.5% (95% CI 3.4 to 25.7). Median progression-free survival was 3.2 months. Progression-free survival rates at 6 and 12 months were 25% and 7.5%, respectively. Two patients diagnosed with recurrent low-grade serous ovarian cancer experienced long-term disease stabilization for more than 37 and 9 months, triggering a review of 12 additional low-grade serous ovarian cancer patients treated outside of the phase II trial. Exploratory tumor genomic profiling revealed potential predictors of sensitivity (CDKN2A deletion) or resistance (CCNE1 amplification or RB1 deletion), which require additional independent validation. Palbociclib demonstrated only modest clinical activity in unselected patients with ovarian cancer. However, cyclin-dependent kinases 4/6 inhibition showed promising clinical activity in low-grade serous ovarian cancer, warranting further study in this subtype. Further biomarker analyses may facilitate patient selection in high-grade serous ovarian cancer.