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Does multilocus inherited neoplasia alleles syndrome have severe clinical expression?
  1. Agostina Stradella1,2,3,
  2. Jesús del Valle1,2,4,
  3. Paula Rofes1,4,2,
  4. Lídia Feliubadaló1,4,2,
  5. Èlia Grau Garces1,2,
  6. Àngela Velasco5,
  7. Sara González1,4,2,
  8. Gardenia Vargas1,4,2,
  9. Ángel Izquierdo5,
  10. Olga Campos1,4,2,
  11. Eva Tornero1,4,2,
  12. Matilde Navarro1,2,
  13. Judith Balmaña-Gelpi6,
  14. Gabriel Capellá1,4,2,
  15. Marta Pineda1,4,2,
  16. Joan Brunet1,5,7,
  17. Conxi Lázaro1,4,2
  1. 1Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
  2. 2Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
  3. 3Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
  4. 4Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
  5. 5Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, Girona, Spain
  6. 6High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain
  7. 7Medical Sciences Department, School of Medicine, University of Girona, Girona, Spain
  1. Correspondence to Dr Joan Brunet and Dr Conxi Lázaro, Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona 08907, Spain; jbrunet{at}iconcologia.net, clazaro{at}iconcologia.net

Abstract

Importance Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.

Objective To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel.

Patients and methods A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses.

Results Thirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene.

Conclusions and relevance Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.

  • multilocus inherited neoplasia alleles syndrome
  • genetic testing
  • cancer syndromes
  • gene panel

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Footnotes

  • Contributors Planning the project: CL, JB, JBG, GC, AS and JdV. Preparation of samples for further study: OC. Analysis of the mutations found in the sequencing and checking by Sanger: JdV, PR, LF, SG, GV, ET and CL. Correlation of the findings with the clinic of the individuals studied and their families: AS, JdV, LF, ÈGG, SG, ÀI, ET, MN, JBG, MP, JB and CL. Genetic counselling: ÈGG, ÀV, ÀI, MN and AS. Global analysis of the results and preparation of the manuscript: AS, JdV, ÈGG, JB, LF, MP and CL.

  • Funding Contract grant sponsor: Supported by the Carlos III National Health Institute and Ministerio de Educación y Ciencia funded by FEDER funds–a way to build Europe (PI16/00563, PI16/01363, SAF2015-68016-R and CIBERONC); the Government of Catalonia (Pla estratègic de recerca i innovació en salut (PERIS), 2017SGR1282 and 2017SGR496); and the scientific foundation Asociación Española Contra el Cáncer.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Comité de Ética de Investigación Clínica del Hospital Universitari de Bellvitge.

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

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