A pan-cancer compendium of chromosomal instability.

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a hallmark of cancer; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types.

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs.

Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare.

Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity.

Inherited renal cell carcinoma (RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbor variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbor mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC ≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been prescreened for pathogenic variants in the major RCC genes.

Characterization of renal cell carcinoma-associated constitutional chromosome abnormalities by genome sequencing.

Constitutional translocations, typically involving chromosome 3, have been recognized as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterized the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC.

SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.

The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families.

Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.

Context: The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare.

Objective: To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series.

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity.

Purpose: To evaluate the role of germline mutation analysis by (1) comprehensive literature review, (2) description of novel germline mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.

Patients And Methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform.

The synthesis and crystal structures of halogenated tolans p-X-C6H4-C[triple bond]C-C6F5 and p-X-C6F4-C[triple bond]C-C6H5(X=F, Cl, Br, I).

A series of halogenated, partially fluorinated tolans of general formula p-X-C6H4-C[triple bond]C-C6F5[X=I (1), Br (2), Cl (3), F (4)] and p-X-C6F4-C[triple bond]C-C6H5[X=I (5), Br (6)] have been prepared via palladium-catalysed Sonogashira cross-coupling, or for X=Cl (7), by nucleophilic aromatic substitution reactions. The single-crystal X-ray structures of 1-3 and 5-6 have been determined. The structures reveal that the molecular packing is characterized by either arene-perfluoroarene interactions (3), or halogen-halogen interactions (isomorphous 1 and 2), or neither (isomorphous 5 and 6).

Correspondence between molecular functionality and crystal structures. Supramolecular chemistry of a family of homologated aminophenols.

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. These compounds are divided into three groups: (a) compounds 1-5 with methylene spacers of the general type HO-C6H4-(CH2)n-C6H4-NH2 (n = 1 to 5) and both OH and NH2 in a para position; (b) compounds 1a, 2a, 2b, 2c, and 3a in which one or more of the methylene linkers in 1 to 3 are exchanged with an S-atom; and (c) compounds 2d, 1b, and 6a prepared with considerations of crystal engineering and where the crystal structures may be anticipated on the basis of structures 1-5,1a, 2a, 2b, 2c, and 3a. These 13 aminols can be described in terms of three major supramolecular synthons based on hydrogen bonding between OH and NH2 groups: the tetrameric loop or square motif, the infinite N(H)O chain, and the beta-As sheet.