Human Genetics

, Volume 136, Issue 11–12, pp 1431–1444 | Cite as

Expanding the spectrum of germline variants in cancer

  • Abdul K. Siraj
  • Tariq Masoodi
  • Rong Bu
  • Sandeep Kumar Parvathareddy
  • Ismail A. Al-Badawi
  • Nasser Al-Sanea
  • Luai H. Ashari
  • Alaa Abduljabbar
  • Samar Alhomoud
  • Saif S. Al-Sobhi
  • Asma Tulbah
  • Dahish Ajarim
  • Khalid Alzoman
  • Muna Aljuboury
  • Hussam Bin Yousef
  • Mohammed Al-Dawish
  • Fouad Al-Dayel
  • Fowzan S. AlkurayaEmail author
  • Khawla S. Al-KurayaEmail author
Original Investigation


Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond “classical” hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.



We thank Zeeshan Qadri and Sarah Siraj for bioinformatics help, Wael Haqawi and Nabil Siraj for sanger sequencing, Ingrid Francesca Victoria, Dionne Rae Rala, Maha Al Rasheed, Khadija Al Obaisi, Mark Ranier Diaz, Allianah D. Benito and Maria Angelita A. Sabido for technical assistance. We acknowledge the support of the Saudi Human Genome Program.

Author Contribution

K.S.A., F.S.A. designed and executed the work; A.K.S., T.M., R.B., S.K.P., F.S.A., K.S.A. performed research, data analysis and wrote the manuscript; I.A.A., N.A., L.H.A., A.A.J., S.A., S.S.A., A.T., D.A., K.A., M.A., H.B.Y., M.A., F.A. collected samples, clinical data related to the study and helped in writing the manuscript. All authors reviewed, edited and approved the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.



Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Abdul K. Siraj
    • 1
  • Tariq Masoodi
    • 1
  • Rong Bu
    • 1
  • Sandeep Kumar Parvathareddy
    • 1
  • Ismail A. Al-Badawi
    • 2
  • Nasser Al-Sanea
    • 3
  • Luai H. Ashari
    • 3
  • Alaa Abduljabbar
    • 3
  • Samar Alhomoud
    • 3
  • Saif S. Al-Sobhi
    • 3
  • Asma Tulbah
    • 4
  • Dahish Ajarim
    • 5
  • Khalid Alzoman
    • 6
  • Muna Aljuboury
    • 7
  • Hussam Bin Yousef
    • 6
  • Mohammed Al-Dawish
    • 6
  • Fouad Al-Dayel
    • 4
  • Fowzan S. Alkuraya
    • 8
    • 9
    • 10
    Email author
  • Khawla S. Al-Kuraya
    • 1
    Email author
  1. 1.Human Cancer Genomic ResearchKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  2. 2.Department of Obstetrics and GynecologyKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  3. 3.Department of Surgery and Colorectal SectionKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  4. 4.Department of Pathology and Laboratory MedicineKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  5. 5.Department of Oncology CentreKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  6. 6.Department of Endocrine SurgeryPrince Sultan Military Medical CityRiyadhSaudi Arabia
  7. 7.Department of PathologyPrince Sultan Military Medical CityRiyadhSaudi Arabia
  8. 8.Department of GeneticsKing Faisal Specialist Hospital and Research CentreRiyadhSaudi Arabia
  9. 9.Department of Anatomy and Cell Biology, College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
  10. 10.Saudi Human Genome ProgramKing Abdulaziz City for Science and TechnologyRiyadhSaudi Arabia

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