Comparison of Large, Medium, and Small Solid Tumor Gene Panels for Detection of Clinically Actionable Mutations in Cancer.

BACKGROUND: Next-generation sequencing of gene panels has supplanted single-gene testing for cancer molecular diagnostics in many laboratories. Considerations for the optimal number of genes to assess in a panel depend on the purpose of the testing. OBJECTIVE: To address the optimal size for the identification of clinically actionable variants in different-sized solid tumor sequencing panels. PATIENTS AND METHODS: Sequencing results from 480 patients with a large, 315 gene, panel were compared against coverage of a medium, 161 gene, and small, 50 gene, panel. RESULTS: The large panel detected a total of 2072 sequence variants in 480 patient specimens; 61 (12.7%) contained variants for which there is therapy approved by the US Food and Drug Administration, 89 (18.5%) had variants associated with an off-label therapy, and 312 (65.0%) contained variants eligible for a genomically matched clinical trial. The small panel covered only 737 of the 2072 variants (35.5%) and somewhat fewer therapy-related variants (on-label 88.5%, off-label 60.7%). The medium-size panel included 1354 of the 2072 (65.3%) variants reported by the large panel. All 318 patients with a clinically actionable variant would have been identified by the medium panel. CONCLUSIONS: The results demonstrate that a carefully designed medium size gene panel is as effective as a large panel for the detection of clinically actionable variants and can be run by most molecular pathology laboratories.

IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass.

Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass (PBM). Insulin-like growth factor type 1 (IGF-1) levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells (MSCs) from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition.