Abdulrahman Alsultan1, Mohammed Essa2,3, Abdullah Aljefri4, Mouhab Ayas4, Musa Alharbi5, Nawaf Alkhayat6, Faisal Al-Anzi7, Fawwaz Yassin8, Fawaz Alkasim9, Qasim Alharbi10, Shaker Abdullah11, Wasil Jastaniah11,12. 1. Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 2. Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Riyadh, Saudi Arabia. 3. College of Medicine, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 4. Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 5. Department of Pediatric Hematology/Oncology, Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia. 6. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 7. Prince Faisal Bin Bandar Cancer Center, Qassim, Saudi Arabia. 8. Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. 9. King Saud Medical City, Riyadh, Saudi Arabia. 10. Department of Pediatric Hematology/Oncology, King Fahad Specialist Hospital, Dammam, Saudi Arabia. 11. Department of Oncology, Princess Noorah Oncology Center, King Saud Bin Abdulaziz University and King Abdulaziz Medical City, Jeddah, Saudi Arabia. 12. Department of Pediatrics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Abstract
BACKGROUND: The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. METHODS: Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. RESULTS: Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. CONCLUSIONS: Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.
BACKGROUND: The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. METHODS: Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. RESULTS: Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. CONCLUSIONS:Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.
Authors: Nadyah A Owaidhah; Zakaria Y Khawaji; Mohammed A Alahmadi; Ahmad S Badawi; Ghazi H Mogharbel; Osama N Makhdoom Journal: Cureus Date: 2022-08-19