Clinical and genomic analyses of neuroendocrine neoplasms of the breast.

Breast neuroendocrine neoplasms (NENs) constitute a rare histologic subtype that includes both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). In this study, we aimed to gain insight into the clinical and molecular characteristics of NENs of the breast. NEN and paired distant normal fresh tissues and clinicopathological data were obtained from 17 patients with NENs, and clinicopathological data were collected from 755 patients with invasive breast carcinomas of no special type (IBCs-NST). We compared the clinicopathological characteristics of NENs and IBCs-NST and performed whole-exome sequencing (WES) of both NEN and paired normal tissues. Compared with the IBC-NST patients, the NEN patients had a higher mean age, lower clinical stage, and lower pathological nodal (pN) stage (P < 0.001, P < 0.001, and P = 0.017, respectively). The most frequently mutated gene in NENs was KMT2C (3/17, 17.6%). NENs had copy number variations (CNVs) of 8q, 11q, and 17q amplification and 17q and 11q deletion and harbored the following specific genes related to tumorigenesis: (i) suppressor genes with loss of heterozygosity (LOH) such as ACE (2/17, 11.8%); (ii) tumor driver genes such as GATA3 (2/17, 11.8%); and (iii) susceptibility genes such as MAP3K4 (17/17, 100%) and PDE4DIP (17/17, 100%). The oncogenic/likely oncogenic mutations of NETs in PI3K pathway genes (50.0%, 18.2%; P < 0.001) and MAPK signaling pathway genes (83.3%, 18.2%; P = 0.035) affected higher proportions than those of NECs. In conclusion, this study provides certain clinical and molecular evidence supporting NENs as a distinct subtype of breast cancer and provides some potential molecular features for distinguishing NETs from NECs.

A Tetra-amido-Protected Ge5-Spiropentadiene.

The first isolable Ge5-spiropentadiene 1 was synthesized via the reduction of (iPr3Si)2NGeCl (3) with potassium. The crystal structure of 1 reveals a spirocyclic Ge5 skeleton containing two Ge-Ge double bonds (avg. 2.34 Å), which are fettered in two Ge3 rings with a dihedral angle of 70.193°. The DFT calculations and orbital analysis show that the σ-delocalization of the Ge5 skeleton and the 2π-delocalized aromatic Ge3 rings enhance the stability of molecule 1.

Types of Six-Membered N-Heterocyclic Germanium Radicals: A Combined Computational and Experimental Study.

A new stable six-membered cyclic germylene radical C (•L3Ge:; •L3 = •[CH3C(PhCN-Dip)2]2-, where Dip = 2,6- iPr2C6H3) has been synthesized and structurally characterized. Unlike the germanium-centered radical A (L1•Ge:, L1 = [HC( tBuCN-Dip)2]-), C is a π-type radical with spin density mainly distributed on the NC3N backbone, similar to that in the germylene radical B (•L2Ge:; •L2 = •[PhC(PhCN-Dip)2]2-). The electronic effects in six-membered N-heterocyclic germanium radicals were systematically investigated using density functional theory calculations. The type of radical, which basically depends on the strong inductive effect of substituents on the side C atoms of the NC3N backbone, is confirmed by monitoring the change in the ordering of the frontier molecular orbitals during radical formation. However, the radical with moderately electronegative substituents or two substituents with comparable electron pushing and pulling abilities could not be isolated in experiments, probably because of the kinetic instability during the reduction process from the germylene chloride precursor to radical.

GeI-GeI Coupling Reaction Induced by a Mixture of CoBr2 and a Seven-Membered N-Heterocyclic Carbene.

A new digermylene has been synthesized through the reaction of a six-membered cyclic radical germylene precursor with a mixture of CoBr2 and a seven-membered N-heterocyclic carbene. The density functional theory simulation on the geometry of the digermylene agrees well with the experimental X-ray diffraction result. The digermylene possesses the shortest GeI-GeI bond [2.4853(6) Å] compared to the known singly bonded analogues, which can be attributed to σ → π* conjugation. In addition, it is revealed that a stable dative bond cannot form for the reductive radical germylene with the oxidative metal centers.