Assessment of genomic alterations in non-syndromic von Hippel-Lindau: Insight from integrating somatic and germline next generation sequencing genomic data.

Von Hippel-Lindau (VHL) syndrome is a hereditary cancer genetic condition associated with inactivating pathogenic alterations in the VHL tumor suppressor gene located at 3p (short arm of chromosome 3). Classic features of VHL include clear cell renal cell carcinoma, hemangioblastomas of the brain, spinal cord, and retina, pheochromocytoma, pancreatic cysts, and neuroendocrine tumors. Two sets of genomic information may be available from patients with VHL: the germline data showing the constitutional genetic profile and somatic profile obtained from patient tumor(s). Here we present both somatic and germline dataset from heterozygous carriers of germline VHL variants who exhibit non-syndromic VHL phenotypes. This data description article accompanies the paper "Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: an integrated evaluation of germline and somatic genomic results'' by Huma Q. Rana, Diane R. Koeller, Alison Schwartz, Danielle K. Manning, Katherine A. Schneider, Katherine M. Krajewski, Toni K. Choueiri, Neal I. Lindeman, Judy E. Garber, Arezou A. Ghazani. We provide next generation sequencing (NGS) data obtained from DNA from tumors (renal cancer, bladder cancer, and cerebral hemangioblastoma) of three VHL carriers. The somatic dataset was analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs) in 447 cancer genes, and structural variation (SVs) in 191 regions across 60 genes for rearrangements. We also present germline raw NGS data and analyzed SNV and CNV data in exonic regions of 133 hereditary cancer genes obtained from the peripheral blood of two VHL carriers.

Cost-effectiveness of multiplexed predictive biomarker screening in non-small-cell lung cancer.

INTRODUCTION: Population-wide screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements to inform cancer therapy in non-small-cell lung cancer (NSCLC) is recommended by guidelines. We estimated cost-effectiveness of multiplexed predictive biomarker screening in metastatic NSCLC from a societal perspective in the United States. METHODS: We constructed a microsimulation model to compare the life expectancy and costs of multiplexed testing and molecularly guided therapy versus treatment with cisplatin-pemetrexed (CisPem). All testing interventions included a two-step algorithm of concurrent EGFR mutation and ALK overexpression testing with immunohistochemistry followed by ALK rearrangement confirmation with a fluorescence in situ hybridization assay for immunohistochemistry-positive results. Three strategies were included: "Test-treat" approach, where molecularly guided therapy was initiated after obtainment of test results; "Empiric switch therapy," with concurrent initiation of CisPem and testing and immediate switch to test-result conditional treatment after one cycle of CisPem; and "Empiric therapy" approach in which CisPem was continued for four cycles before start of a tyrosine kinase inhibitor. RESULTS: The incremental cost-effectiveness ratio for "Test-treat" compared with treatment with CisPem was $136,000 per quality-adjusted life year gained. Both empiric treatment approaches had less favorable incremental cost-effectiveness ratios. "Test-treat" and "Empiric switch therapy" yielded higher expected outcomes in terms of quality-adjusted life years and life-years than "Empiric therapy." These results were robust across plausible ranges of model inputs. CONCLUSION: From a societal perspective, our cost-effectiveness results support the value of multiplexed genetic screening and molecularly guided therapy in metastatic NSCLC.

Comparative response assessment by serum immunoglobulin M M-protein and total serum immunoglobulin M after treatment of patients with Waldenström macroglobulinemia.

Serum immunoglobulin (Ig) M monoclonal protein determined by electrophoresis (sIgM-MP) and total serum IgM (sIgM) by nephelometry are widely used for response assessment in Waldenström macroglobulinemia (WM), although have not been compared for predicting changes in underlying disease burden. We, therefore, compared these serum markers with changes in bone marrow (BM) and extramedullary disease for 73 patients who were rituximab naive and treated with a rituximab-containing regimen. By linear regression analysis, reductions in sIgM-MP and sIgM showed moderate correlation with BM disease involvement (r = 0.4051 and r = 0.4490, respectively), and did not differ from one another as estimators of BM disease response (P = .3745). Neither sIgM-MP nor sIgM showed a strong correlation with BM disease response in patients with low (<1000 mg/dL) or high (>5000 mg/dL) IgM levels and extramedullary disease response. sIgM-MP and sIgM, therefore, are comparable response markers in WM. Development of newer, more accurate surrogate response markers are needed to better delineate treatment outcomes in patients with WM and with low or high IgM levels, and extramedullary disease.