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Open Access 01-12-2019 | Research

Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Authors: Marta Ramírez-Calvo, Zaida García-Casado, Antonio Fernández-Serra, Inmaculada de Juan, Sarai Palanca, Silvestre Oltra, José Luis Soto, Adela Castillejo, Víctor M Barbera, Ma José Juan-Fita, Ángel Segura, Isabel Chirivella, Ana Beatriz Sánchez, Isabel Tena, Carolina Chaparro, Dolores Salas, José Antonio López-Guerrero

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2019

Abstract

Background

Approximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting.

Methods

A multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines.

Results

Nineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1).

Conclusions

Overall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.

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Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23(38):6445–70. https://doi.org/10.1038/sj.onc.1207714.CrossRefPubMed

Guan Y, Hu H, Peng Y, et al. Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing. Familial Cancer. 2015;14(1):9–18. https://doi.org/10.1007/s10689-014-9749-9.CrossRefPubMed

Stanislaw C, Xue Y, Wilcox WR. Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing. Cancer biol med. 2016;13(1):55–67. https://doi.org/10.28092/j.issn.2095-3941.2016.0002.CrossRefPubMedPubMedCentral

Rahner N, Steinke V. Hereditary cancer syndromes. Dtsch Arztebl Int. 2008;105(41):706–14. https://doi.org/10.3238/arztebl.2008.0706.CrossRefPubMedPubMedCentral

Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23(2):276–92. https://doi.org/10.1200/JCO.2005.10.042.CrossRefPubMed

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentral

Simbolo M, Mafficini A, Agostini M, et al. Next-generation sequencing for genetic testing of familial colorectal cancer syndromes. Hered Cancer Clin Pract. 2015;13(1):18. https://doi.org/10.1186/s13053-015-0039-9.CrossRefPubMedPubMedCentral

Kraus C, Hoyer J, Vasileiou G, et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017;140(1):95–102. https://doi.org/10.1002/ijc.30428.CrossRefPubMed

Judkins T, Leclair B, Bowles K, et al. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer. 2015;15:215. https://doi.org/10.1186/s12885-015-1224-y.CrossRefPubMedPubMedCentral

10.

Slavin TP, Niell-Swiller M, Solomon I, et al. Clinical application of multigene panels: challenges of next-generation counseling and Cancer risk management. Front Oncol. 2015;5:208. https://doi.org/10.3389/fonc.2015.00208.CrossRefPubMedPubMedCentral

11.

Tung N, Lin NU, Kidd J, et al. Frequency of germline mutations in 25 Cancer susceptibility genes in a sequential series of patients with breast Cancer. J Clin Oncol. 2016;34(13):1460–8. https://doi.org/10.1200/JCO.2015.65.0747.CrossRefPubMedPubMedCentral

12.

Hall MJ, Obeid E, Daly MB. Multigene panels to evaluate hereditary Cancer risk: reckless or relevant? J Clin Oncol. 2016;34(34):4186–7. https://doi.org/10.1200/JCO.2016.68.6725.CrossRefPubMed

13.

Maxwell KN, Wubbenhorst B, D'Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015;17(8):630–8. https://doi.org/10.1038/gim.2014.176.CrossRefPubMed

14.

de Juan I, Esteban E, Palanca S, Barragán E, Bolufer P. High-resolution melting analysis for rapid screening of BRCA1 and BRCA2 Spanish mutations. Breast Cancer Res Treat. 2009;115(2):405–14. https://doi.org/10.1007/s10549-008-0073-7.CrossRefPubMed

15.

Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43(9):879–82. https://doi.org/10.1038/ng.893.CrossRefPubMedPubMedCentral

16.

Thompson ER, Rowley SM, Sawyer S, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS One. 2013;8(1):e54772. https://doi.org/10.1371/journal.pone.0054772.CrossRefPubMedPubMedCentral

17.

Gutiérrez-Enríquez S, Bonache S, de Garibay GR, et al. About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. Int J Cancer. 2014;134(9):2088–97. https://doi.org/10.1002/ijc.28540.CrossRefPubMed

18.

Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165–7. https://doi.org/10.1038/ng1959.CrossRefPubMed

19.

Erkko H, Xia B, Nikkilä J, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446(7133):316–9. https://doi.org/10.1038/nature05609.CrossRefPubMed

20.

Tischkowitz M, Xia B, Sabbaghian N, et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A. 2007;104(16):6788–93. https://doi.org/10.1073/pnas.0701724104.CrossRefPubMedPubMedCentral

21.

Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian Cancer genes in more than 1000 patients. J Mol Diagn. 2015;17(5):533–44. https://doi.org/10.1016/j.jmoldx.2015.04.009.CrossRefPubMed

22.

Win AK, Dowty JG, Cleary SP, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146(5): 1208-11.e1-5. 2014. https://doi.org/10.1053/j.gastro.2014.01.022.

23.

Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009;27(24):3975–80. https://doi.org/10.1200/JCO.2008.21.6853.CrossRef

24.

Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41(1):1–8. https://doi.org/10.1016/j.ctrv.2014.10.008.CrossRefPubMed

25.

Desmond A, Kurian AW, Gabree M, et al. Clinical Actionability of multigene panel testing for hereditary breast and ovarian Cancer risk assessment. JAMA Oncol. 2015;1(7):943–51. https://doi.org/10.1001/jamaoncol.2015.2690.CrossRefPubMed

Title: Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)
Authors: Marta Ramírez-Calvo
Zaida García-Casado
Antonio Fernández-Serra
Inmaculada de Juan
Sarai Palanca
Silvestre Oltra
José Luis Soto
Adela Castillejo
Víctor M Barbera
Ma José Juan-Fita
Ángel Segura
Isabel Chirivella
Ana Beatriz Sánchez
Isabel Tena
Carolina Chaparro
Dolores Salas
José Antonio López-Guerrero
Publication date: 01-12-2019
Publisher: BioMed Central
Published in: Hereditary Cancer in Clinical Practice / Issue 1/2019
Electronic ISSN: 1897-4287
DOI: https://doi.org/10.1186/s13053-019-0104-x

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