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

      research-article
      1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 2 , 3 , 1 , 4 , 5 , 6 , 7 , 8 , 1 , 1 , 2 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 10 , 16 , 5 , 17 , 18 , 19 , 11 , 10 , 9 , 1 , 2 , 9 , 20 , 21 , 22 , 4 , 5 , 23 , 14 , 11 , NIHR BioResource Rare Diseases Consortium 2 , 1 , 2 , 1 , 2 ,
      American Journal of Human Genetics
      Elsevier
      cancer-predisposition syndromes, inherited cancer genetics, genetic testing, whole-genome sequencing

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          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 2 = 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.

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          Most cited references18

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          Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants.

          We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ∼3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.
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            Realizing the promise of cancer predisposition genes.

            Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.
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              Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

              Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.
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                Author and article information

                Contributors
                Journal
                Am J Hum Genet
                Am. J. Hum. Genet
                American Journal of Human Genetics
                Elsevier
                0002-9297
                1537-6605
                05 July 2018
                14 June 2018
                : 103
                : 1
                : 3-18
                Affiliations
                [1 ]University of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
                [2 ]NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
                [3 ]Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
                [4 ]Department of Clinical Genetics, Princess Anne Hospital, Southampton SO16 5YA, UK
                [5 ]North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK
                [6 ]Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK
                [7 ]Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK
                [8 ]Peninsula Clinical Genetics, Royal Devon & Exeter Hospital, Exeter EX1 2ED, UK
                [9 ]East Anglian Medical Genetics Service, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
                [10 ]West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK
                [11 ]Manchester 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
                [12 ]Molecular Diagnostics Laboratory, National Centre of Scientific Research “Demokritos,” Athens, Greece
                [13 ]Department of Clinical Genetics, Liverpool Women’s Hospital, Liverpool L8 7SS, UK
                [14 ]Department of Clinical Genetics, St. George’s Hospital, London SW17 0QT, UK
                [15 ]Northern Genetics Service, Newcastle upon Tyne Hospitals, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK
                [16 ]Department of Clinical Genetics, Guy’s and St. Thomas’ Hospital, London SE1 9RT, UK
                [17 ]Division of Breast Surgery, University of Hong Kong, Pokfulam, Hong Kong
                [18 ]Hong Kong Hereditary Breast Cancer Family Registry, Shau Kei Wan, Hong Kong
                [19 ]Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
                [20 ]Clinical Genetics Institute, Kaplan Medical Center, Rehovot 76100, Israel
                [21 ]Hebrew University and Hadassah Medical Center, Jerusalem, Israel
                [22 ]Department of Clinical Genetics, Nottingham University Hospitals, City Hospital, Nottingham NG5 1PB, UK
                [23 ]Department of Clinical Genetics, Aarhus University Hospital, Aarhus 8200, Denmark
                Author notes
                []Corresponding author erm1000@ 123456medschl.cam.ac.uk
                Article
                S0002-9297(18)30160-5
                10.1016/j.ajhg.2018.04.013
                6037202
                29909963
                8c977227-d52c-4a2c-92f3-b61cf9afb674
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 6 December 2017
                : 25 April 2018
                Categories
                Article

                Genetics
                cancer-predisposition syndromes,inherited cancer genetics,genetic testing,whole-genome sequencing

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