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Original research
Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders
  1. Estela Carrasco1,2,3,
  2. Adrià López-Fernández1,3,
  3. Marta Codina-Sola4,5,6,
  4. Irene Valenzuela4,5,6,
  5. AM Cueto-González4,5,6,
  6. Guillermo Villacampa7,
  7. Victor Navarro7,
  8. Sara Torres-Esquius3,
  9. Dolors Palau4,6,
  10. Mara Cruellas1,3,
  11. Maite Torres1,
  12. Belen Perez-Dueñas8,9,
  13. Anna Abulí4,5,6,
  14. Orland Diez3,4,6,
  15. Constantino Sábado-Álvarez10,
  16. Elena García-Arumí4,5,6,9,11,
  17. Eduardo F Tizzano4,5,6,
  18. Lucas Moreno10,12,
  19. Judith Balmaña1,3,13
  1. 1Hereditary Cancer Genetics Group, Medical Oncology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
  2. 2Department of Pediatrics, Obstetrics and Gynecology, Preventative Medicine and Public Health, Autonomous University of Barcelona, Barcelona, Spain
  3. 3Hereditary Cancer Genetics Group, Medical oncology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035, Barcelona, Spain
  4. 4Department of Clinical and Molecular Genetics, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
  5. 5Medicine Genetics Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
  6. 6Member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516], ERN-ITHACA, Barcelona, Spain
  7. 7Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035, Barcelona, Spain
  8. 8Paediatric Neurology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Universitat Autónoma de Barcelona, Barcelona, Spain
  9. 9Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
  10. 10Department of Pediatric Oncology and Hematology, Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035, Barcelona, Spain
  11. 11Research Group on Neuromuscular and Mitochondrial Disorders, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
  12. 12Childhood Cancer and Blood Disorders Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
  13. 13Member of the European Reference Network on GENTURIS, ID: HP-ERN-2016 739547, GENTURIS, Barcelona, Spain
  1. Correspondence to Dr Lucas Moreno, Pediatrics Oncology and Hematology Division, Vall d'Hebron University Hospital, Barcelona, 08035, Spain; lucas.moreno{at}vallhebron.cat

Abstract

Background/Objectives Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls).

Methods This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method.

Results The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2, three PMS2, two SDHB, and one each in BRCA1, MLH1 and RAD51C. Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001).

Conclusion SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history.

  • Genetic Testing
  • Genetics, Medical
  • Disease Management
  • Genetic Predisposition to Disease
  • Genetic Counseling

Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Twitter @Estela131516

  • Contributors Conceptualisation: EC, JB, LM. Data curation: EC, ST-E, MC-S, IV, AMC-G, DP, AA. Formal analysis: GV, VN, EC. Funding acquisition: Not fundings. Investigation: EC, JB, LM. Methodology: EC, JB, LM, GV, VN. Project administration: EC. Resources: ST-E, MC-S, CS-A, OD, DP, MC, AMC-G, IV, BP-D, EFT, MT, EG-A, Genetica Software: ST-E, GV, VN. Supervision: JB-G, LM, EG-A, EFT. Validation: EC, JB, LM. Visualisation: EC, GV. Writing: EC, VN, GV, JB, LM, AL-F. Guarantor: EC, JB, LM. Writing review and editing: all authors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests JB has received a speaker’s fee from AstraZeneca and Pfizer and has served AstraZeneca in an advisory role. GV has received a speaker’s fee/research honoraria from MSD and Pierre Fabre and has served AstraZeneca in an advisory role. LM is member of the data monitoring committees for clinical trials sponsored by Novartis, Actuate Therapeutics, Shionogi, Incyte, University of Southampton and Royal Marsden NHS Foundation Trust; had a consulting role for Novartis, Norgine, Boehringer, Y-mAbs and Shionogi; and participated in educational activities organised by Bayer and Eusa Pharma. LM is member of the Executive Committee of SIOPEN (European neuroblastoma research cooperative group), an organisation which receives royalties for sales of dinutuximab beta. EFT has received grant support to conduct clinical trials on SMA from Ionis/Biogen and serves as a consultant to Biogen, Novartis, AveXis, Roche, Biologix and Cytokinetics.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.