ArticleAmerican journal of human genetics2018
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
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Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed.
- Multiple Primary Cancer Incidence by County-Level Smoking Prevalence among U.S. Cancer Survivors.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026Article
- Clinical and genetic features of multiple primary tumours cohorts with a renal cell carcinoma: Implications for molecular genetic investigations.International journal of cancer · 2025Article
- Multiple Primary Cancers as an Independent Criterion for Germline Testing: Comparison with Guideline-Based Criteria.Journal of clinical medicine · 2025Article
- Tuberous Sclerosis Complex Caused byAnnals of laboratory medicine · 2025Article
- Genetic testing referral and germline pathogenic variants in patients with breast cancer and another non-breast cancer.Cancer genetics · 2025Article
- Exome-based cancer predisposition gene testing can provide a genetic diagnosis for individuals with heterogeneous tumor phenotypes.European journal of human genetics : EJHG · 2025Article
- Article
- Prevalence of Constitutional Pathogenic Variant in a Cohort of 348 Patients With Multiple Primary Cancer Addressed in Oncogenetic Consultation.Molecular genetics & genomic medicine · 2025Article
- Genetic evaluation of patients with multiple primary cancers.Oncology letters · 2025Article
- Multiple Primary Cancers With Hematologic Malignancies and Germline Predisposition: A Case Series.Annals of laboratory medicine · 2024Article
- Single variant, yet "double trouble": TSC and KBG syndrome because of a large de novo inversion.Life science alliance · 2024Article
- Germline whole genome sequencing in adults with multiple primary tumors.Familial cancer · 2023Article
- Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer.Human genomics · 2023Article
- Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.Journal of endocrinological investigation · 2023Article
- Complete response to chemoimmunotherapy with bevacizumab in synchronous multiple primary cancers: pulmonary adenocarcinoma and sarcomatoid carcinoma.Cold Spring Harbor molecular case studies · 2023Article
- High prevalence of reduced fertility and use of assisted reproductive technology in a German cohort of patients with peripartum cardiomyopathy.Clinical research in cardiology : official journal of the German Cardiac Society · 2023Article
- Hereditary cancer syndromes.World journal of clinical oncology · 2023Review
- Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea.Human genomics · 2023Review
- Clinical and Genetic Analysis of Multiple Osteochondromas in A Cohort of Argentine Patients.Genes · 2022Article
- Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.Human molecular genetics · 2022Article
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Authors and funding
44 authors.
James WhitworthUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Philip S SmithUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Jose-Ezequiel MartinUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Hannah WestUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Andrea LuchettiUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Faye RodgerUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Graeme ClarkUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Keren CarssNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Jonathan StephensNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Kathleen StirrupsNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Chris PenkettNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Rutendo MapetaNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Sofie AshfordNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Karyn MegyNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.
Hassan ShakeelUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Munaza AhmedDepartment of Clinical Genetics, Princess Anne Hospital, Southampton SO16 5YA, UK; North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
Julian AdlardYorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
Julian BarwellDepartment of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
Carole BrewerPeninsula Clinical Genetics, Royal Devon & Exeter Hospital, Exeter EX1 2ED, UK.
Ruth T CaseyUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Ruth ArmstrongUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; East Anglian Medical Genetics Service, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Trevor ColeWest Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK.
Dafydd Gareth EvansManchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, UK.
Florentia FostiraMolecular Diagnostics Laboratory, National Centre of Scientific Research "Demokritos," Athens, Greece.
Lynn GreenhalghDepartment of Clinical Genetics, Liverpool Women's Hospital, Liverpool L8 7SS, UK.
Helen HansonDepartment of Clinical Genetics, St. George's Hospital, London SW17 0QT, UK.
Alex HendersonNorthern Genetics Service, Newcastle upon Tyne Hospitals, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
Jonathan HoffmanWest Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK.
Louise IzattDepartment of Clinical Genetics, Guy's and St. Thomas' Hospital, London SE1 9RT, UK.
Ajith KumarNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
Ava KwongDivision of Breast Surgery, University of Hong Kong, Pokfulam, Hong Kong; Hong Kong Hereditary Breast Cancer Family Registry, Shau Kei Wan, Hong Kong; Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
Fiona LallooManchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, UK.
Kai Ren OngWest Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK.
Joan PatersonEast Anglian Medical Genetics Service, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Soo-Mi ParkUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; East Anglian Medical Genetics Service, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Rakefet Chen-ShtoyermanClinical Genetics Institute, Kaplan Medical Center, Rehovot 76100, Israel; Hebrew University and Hadassah Medical Center, Jerusalem, Israel.
Claire SearleDepartment of Clinical Genetics, Nottingham University Hospitals, City Hospital, Nottingham NG5 1PB, UK.
Lucy SideDepartment of Clinical Genetics, Princess Anne Hospital, Southampton SO16 5YA, UK; North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
Anne-Bine SkytteDepartment of Clinical Genetics, Aarhus University Hospital, Aarhus 8200, Denmark.
Katie SnapeDepartment of Clinical Genetics, St. George's Hospital, London SW17 0QT, UK.
Emma R WoodwardManchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, UK.
NIHR BioResource Rare Diseases ConsortiumNIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Marc D TischkowitzUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Eamonn R MaherUniversity of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Electronic address: erm1000@medschl.cam.ac.uk.
Funding
British Heart Foundation FS/10/013/28073British Heart Foundation PG/15/103/31900Medical Research Council G0800671
Abstract
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 (χ
Indexed as
AdultAgedBiomarkers, TumorFemaleGenetic Predisposition to DiseaseGenetic TestingGenetic VariationGerm-Line MutationHumansMaleMiddle AgedNeoplasms, Multiple PrimaryPhenotypeBiomarkers, Tumorcancer-predisposition syndromesgenetic testinginherited cancer geneticswhole-genome sequencing
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