Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Surgical outcomes and national comprehensive cancer network compliance in advanced ovarian cancer surgery in a low volume military treatment facility.

OBJECTIVE: To evaluate the optimal cytoreduction (OPT) rate, National Comprehensive Cancer Network (NCCN) treatment guideline compliance rate and patient outcomes for advanced stage epithelial ovarian cancer (EOC) patients at our low volume institution. METHODS: Following IRB approval, records of patients with Stage III-IV EOC, primary peritoneal, or fallopian tube carcinoma completing both primary surgery and adjuvant chemotherapy were reviewed. Patient demographics, clinicopathologic variables, cytoreduction status (optimal or suboptimal), NCCN treatment guideline compliance, and survival were reviewed. Standard statistical tests including the t-test, Chi-square or Fisher's exact test and Kaplan-Meier Survival curves were utilized. RESULTS: Overall, 48 patients met all inclusion criteria. 35(73%) and 13 (27%) achieved optimal and suboptimal cytoreduction, respectively. Median overall survival (OS) for all patients was 37.1 months (95% CI 23.2 - 51.1 months) and NCCN treatment guideline compliance was 85.4%. Compared to sub-optimally cytoreduced patients the optimally cytoreduced patients were significantly older (62.2 vs. 53.5 yrs; p=0.015); no other significant clinicopathologic differences were observed between the two groups. 19 of 48 (39.6%) patients enrolled in an upfront cooperative group trial. Median OS was 43.4 months for optimally compared to 15.6 months in sub-optimally cytoreduced patients (p=0.012). CONCLUSIONS: NCCN treatment guideline compliance, OPT, and median OS rates in our low volume institution are similar to those reported nationally, and argue against using volume alone as a rationale for centralization of care.

Yin yang 1 modulates taxane response in epithelial ovarian cancer.

Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.