• 2019-07
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  • It is interesting that the overall rate


    It is interesting that the overall rate of consanguinity in our study was 38%, which is no higher than the rate published previously in the general population in Saudi Arabia [16,17]. In addition, only 28 (1.6%) patients had a history of cancer in their siblings, despite having an average size of four children per family, and a family history of Lynch syndrome-associated cancer in first and second degree relatives less than 50 years was observed in only 28 cases (Table 2). These numbers were expected to be higher if CMMRD and other autosomal recessive HCSS susceptibility genes were more prevalent in our population. Thus, consanguinity alone did not seem to increase the overall risk of childhood cancer in our population. This does not preclude the presence of large Spectinomycin in our population who harbour detrimental homozygous founder mutations in genes that predispose to cancer as previously reported in Saudi children with CMMRD [19] and Fanconi anemia [26]. Genetic screening is required to determine the actual prevalence of CMMRD in our population. Among tumors commonly observed in LFS, non-Ewing sarcoma was reported in 106 (6.1%) patients, none of whom had adrenocortical tumors or choroid plexus carcinoma. A family history of LFS-associated cancer was observed in 16 (1%) cases (Table 2). Thus, the overall risk of LFS was approximately 7% in our population. This frequency might be higher if further data were available on some malignancies that frequently have germline TP53 mutations such as acute lymphoblastic leukemia with low hypodiploidy and sonic hedgehog (SHH) medulloblastoma [[27], [28], [29]]. It is important to identify patients with LFS in order to offer tumor surveillance for them and their family members who carry TP53 pathogenic mutations [30]. A recent report showed long term survival benefit with early implementation of a comprehensive cancer-surveillance program for patients with Li-Fraumeni Syndrome. The overall 5-year survival was 88.8% in the surveillance group and 59.6% in the non-surveillance group [10]. Thus optimization of selection criteria for screening and surveillance is required. A family history of cancer diagnosed at any age was reported in 50 (2.9%) first degree, 535 (30.7%) second degree, and 272 (15.6%) third degree relatives. When we limited family history of cancer to age at time of diagnosis of less than 18 years, 26 (1.6%) first degree (mostly siblings), 42 (2.5%) second degree, and 90 (5.4%) third degree relatives had a history of cancer before their 18th birthday. This is comparable to the 1.1% frequency of childhood cancer among first degree and 1.3% frequency among second degree relatives of children with cancer from the Utah population database [12]. The presence of cancer among third degree relatives in our population was not incorporated in our overall HCSS prevalence assessment because ACMG guidelines limited family history to first and second degree relatives. It should be noted that we did not have a control group from our general population to be able to estimate the risk of cancer among family members. Instead, we compared the pattern of cancer among patients with or without a family history of cancer, no differences being observed (Table 4). This observation was true also when comparison was limited to the degree of relatedness (First, second or third degree relatives), age of cancer onset in the affected family member(s) to less than or equal to 45 years, or less than 18 years of age. In addition, presence of consanguinity showed no effect on the frequency and characteristics of family history of cancer (Table 6). Approximately 5% of patients had an associated syndrome or inherited disorder. Down syndrome was the most frequent observed syndrome. Most of the observed cancer types were expected with the associated disorders. However, some associations were not reported previously as shown in Table 1. It is interesting that disorders that show autosomal recessive inheritance, such as Fanconi anemia, were reported in very few cases in our cohort. Among all of our patients, only six had two primary cancers and one of these had Turcot syndrome. This low number might be explained by the short follow up duration and/or by the recent observation of lower cumulative risk of second neoplasm among childhood cancer survivors due to the overall reduction in treatment intensity [31].