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. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

[Christian pamphlets. Vol. 12]

1 v. ; 24 cm.De scholiis Homericis ad historiam fabularem pertinentibus / Eduardus Schwartz -- Zur Stichometrie / Martin Schanz -- Die Iuli Frontini Strategematon libro qui fertur quarto / Gottholdus Gundermann -- Die Traditionen über die Stiftung der olympischen Spiele / P. Knapp -- Die älteste lateinische Inschrfit / P.K. -- Zu den Biographika des Suidas / Adam Daub -- Beiträge zur Erklärung von Wandbildern / Paul Knapp -- Ueber die Schriften des Cornelius Celsus / M. Schanz -- Zu Theognis / Eduard Hiller -- Index lectionum quae in universitate litter. Friederica Guilelma per sem. hib. 1880/1 habebuntur ; Index scholarum in universitate litter. Vratislaviensi per hiemem anni 1880/1 habendarum / Ludwig Martens -- Friedrich Wieseler, Scenische und kritische Bemerkungen zu Euripides' Kyklops / N. Wecklein.Antonius Jannarakis, Annotationes criticae in Longini qui fertur [peri hypsous] libellum / Ludwig Martens -- De Aristophane Byzantio et Suetonio Tranquillo Eustathi auctoribus / Leopold Cohn // Analecta Aristarchea / Adolfus Schimberg -- De M. Tullii Ciceronis Oratione in toga candida habita / Paulus Koetschau -- De figuris quaestiones criticae Part I. / Iohannes Mueller -- Ausonianarum quaestionum specimen primum / Guilelmus Brandes -- Westfälische Volkslieder in Wort und Weise .. / Reinhold Köhler -- August Reinbrecht, Die Legende von den sieben Schläfern und der anglo-normannische Dichter Chardri / H. Varnhagen -- De tropis et figuris apud Tibullum / Marx Hansen -- Bistânî's Encyclopédie arabe / Fleischer -- Tibetan and English dictionary by H.A. Jäschke / G. Th. Reichelt -- Geschichte des Artachšîr i Pâpakan, aus dem Pehlewi übersetzt ... von T. Nöldeke / Alfred von Gutschmid.Schī-kīng. Das kanonische Liederbuch der Chiesen. Aus dem Chinesischen übersetzt und erklärt von Victor von Strauss / V. von Strauss und Torney -- Bemerkungen zu Tabar's Sasanidengeschichte, übersetzt von Th. Nöldeke / Alfred von Gutschmid -- Fabius Pictor und Livius / Eduard Heydenreich -- De Euripideorum prologorum / Iosephus Klinkenberg -- Über den Codex Laurentianus 53, 35, nebst Nachträgen zu den neuesten Forschungen über Ciceros Briefe / Franz Rühl -- Friedrich Christoph Schlosser / Franz Rühl -- Miscellen -- Kritische Bemerkungen / A. Nauck