Frequency of pathogenic/likely pathogenic germline variants in cancer‐related genes among children with acute leukemia in Saudi Arabia

Alsultan, Abdulrahman; Essa, Mohammed F.; Al‐Jefri, Abdullah; Ayas, Mouhab; Alharbi, Musa; Alkhayat, Nawaf; Al-Anzi, Faisal; Yassin, Fawwaz; Alkasim, Fawaz; Alharbi, Qasim; Alaqel, Shaker; Jastaniah, Wasil

doi:10.1002/pbc.28340

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…PMS2 mutations have been rare in Lynch syndrome, probably due to difficulties in their identification, but more recently these have been reported, predisposing to endometrial cancer with a relative risk of about twice higher than for colorectal cancer 23 , 25 – 27 . Recently, PMS2 mutations have been reported also in childhood ALL 21 , 28 . Thus we hypothesize that the associations of ALL with endometrial and rectal cancer may be explained by germline variants in the PMS2 gene.…”

Section: Discussionmentioning

confidence: 99%

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Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations

Sundquist

et al. 2021

Sci Rep

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Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.

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Section: Discussionmentioning

confidence: 99%

“…Breast cancer was one of the associated cancers in families of very young ALL patients, and the Fanconi anemia-BRCA2 pathway is a known risk factor for childhood ALL 2 , 21 . However, if BRCA2 was involved one would expect that ovarian cancer risk was also increased.…”

Section: Discussionmentioning

confidence: 99%

Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations

Sundquist

et al. 2021

Sci Rep

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“…Other studies have shown that hTERT dysregulation was only observed in limited cases of relapsed childhood ALL [82], while a study in Saudi Arabia disclosed that hTERT mutations are not linked to predisposition to childhood acute leukemia [83]. In terms of relevance in disease pathogenesis, studies have shown that in adult T-cell leukemia/lymphoma (ATLL), the activation of telomerase is required for the disease development and progression, while in AML and CML it is only required for maintenance and not initiation [15,84,85].…”

Section: Tert Dysregulation In Leukemiasmentioning

confidence: 98%

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Yik

Aziz

Rajasegaran

et al. 2021

Genes

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The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries.

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“…Despite the fact that the Saudi Arabia community is considered to be highly consanguineous, no significant correlation was observed between the frequency of P/LP mutations among pediatrics with consanguineous parents compared to those who are not. In addition, the study proposed that homozygous germline mutations in cancer predisposition genes are unlikely to play a substantial role in the risk of childhood leukemia [ 22 ].…”

Section: Reviewmentioning

confidence: 99%

Epidemiological Trends and Clinical Characteristics of Childhood Leukemia in Saudi Arabia: A Review

Owaidhah¹,

Khawaji²,

Alahmadi³

et al. 2022

Cureus

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Leukemia is the most prevalent type of cancer among children in Saudi Arabia. It has variable clinical presentations and accounts for a large scale of mortality and morbidity. Acute lymphoblastic leukemia (ALL) constituted the majority of pediatric leukemic cases with male gender predisposition. The most common first presentation that patients come with are manifestations of anemia, thrombocytopenia, and fever. Bone pain, fatigue, weight loss, organomegaly, and pale skin are among the commonest manifestations of pediatric leukemia. Childhood ALL and acute myeloid leukemia (AML) clinical manifestations seem to be very similar, even though there're some considerable differences in how common the clinical characteristics are. Chromosomal abnormalities are taken into consideration to determine survival and treatment. PubMed and Google Scholar were searched for the childhood leukemia population in Saudi Arabia. Our review article aims at providing comprehensible and updated statistical data on the different types of leukemia and their clinical presentations in Saudi Arabia.

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Frequency of pathogenic/likely pathogenic germline variants in cancer‐related genes among children with acute leukemia in Saudi Arabia

Abstract: Background:The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancerrelated genes among children with cancer in highly consanguineous populations is not well studied.

Cited by 3 publications

References 25 publications

Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations

Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations

Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Epidemiological Trends and Clinical Characteristics of Childhood Leukemia in Saudi Arabia: A Review

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