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Expanding the spectrum of germline variants in cancer


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.

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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.

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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.

Correspondence to Fowzan S. Alkuraya or Khawla S. Al-Kuraya.

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Siraj, A.K., Masoodi, T., Bu, R. et al. Expanding the spectrum of germline variants in cancer. Hum Genet 136, 1431–1444 (2017). https://doi.org/10.1007/s00439-017-1845-0

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