Li‐Fraumeni and Li‐Fraumeni—like syndrome among children diagnosed with pediatric cancer in Southern Brazil

Abstract

BACKGROUND: Pediatric cancers are a feature in patients with Li-Fraumeni syndrome and its variant Li-Fraumeni-like syndrome (LFS=LFL). To the best of the authors' knowledge, TP53 germline mutations are currently the only molecular defect known to be associated with this disease. Recently, a specific germline mutation in this gene, p.R337H, has been reported at a high prevalence in Brazil. METHODS: The prevalence of LFS=LFL was investigated in children with cancer who were diagnosed with tumors on the LFS=LFL spectrum and in a small consecutive series of controls without cancer. The prevalence of the germline p.R337H mutation and of other germline TP53 mutations was investigated in a general group of children with cancer and exclusively in children fulfilling the clinical criteria for LFS=LFL, respectively. RESULTS: Among the 65 children without cancer, 1.5% had a family history of LFL whereas of the 292 children with cancer, 25.3% had a family history of LFL (P <.001). Screening for the p.R337H mutation identified 11 carriers (3.7%), 9 of whom were diagnosed with adrenocortical carcinomas (ACC) and 2 of whom were diagnosed with choroid plexus carcinomas. One of the ACC probands was homozygous mutant. The Brazilian founder haplotype and loss of heterozygosity at the p.R337H locus were present in all carriers. In addition, direct sequencing of the entire TP53 coding region and gene rearrangement analysis of probands fulfilling the criteria for LFL (Eeles 2 criteria, Birch and=or Chompret criteria) and who were negative for the p.R337H mutation revealed a DNA-binding domain pathogenic mutation, p.G245S, in 1 child. CONCLUSIONS: TP53 p.R337H testing should be offered to Brazilian children diagnosed with ACC and choroid plexus carcinoma. A significant percentage of children with cancer in southern Brazil fulfill the criteria for LFL and should be referred for genetic risk assessment. Cancer 2013;119:4341-9. V C 2013 American Cancer Society.KEYWORDS: childhood cancer, Li-Fraumeni syndrome, Li-Fraumeni-like syndrome, TP53 mutations, TP53 p.R337H mutation. INTRODUCTIONPediatric cancer is one of the more frequent causes of nontraumatic deaths in children, representing 1% to 3% of all cancer diagnoses worldwide. [1][2][3][4][5] The Brazilian National Cancer Institute estimates that approximately 384,340 new cancer diagnoses will have been made in Brazil in 2012, including 11,530 (3%) diagnosed in children and adolescents aged < 19 years. 5 Childhood cancers that arise within the context of a genetic predisposition are rare events, and are estimated to account for approximately 5% to 10% of all pediatric cancer cases. 5 However, with increased awareness of cancer family history and advanced technologies in mutation detection, this percentage will likely increase, 6 facilitating the presymptomatic identification of high-risk individuals and ultimately decreasing cancer-related mortality in this setting.Childhood cancers are a common feature in patients with Li-Fraumeni syndrome and its variant Li-Fraumeni-like syndrome (LFS...

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

“…60). The prevalence of this variant is particularly high in Southern Brazil, where it can be as high as 0.3% in the general population (61) and is also common in patients with LFS and LFL from this geographical region (62).…”

Surveillance recommendations for patients with germline TP53 mutations

“…The R337H variant that occurs in exon 10 is prevalent among TP53 mutation carriers in Southern Brazil and is strongly associated with ACC [28]. Choroid plexus carcinomas, leukemia and breast cancers also occur at increased incidence in these families [20,29].…”

“…In childhood, the most common cancers are ACC, choroid plexus carcinoma, gliomas and medulloblastoma [16]. An increased incidence of melanoma, lymphoma, pancreatic, lung, prostate and ovarian cancers [7,17] has been recorded with gastric [18] and colorectal cancers [19] and malignant phyllodes breast tumors [20] also possibly associated. Recently, anaplastic rhabdomyosarcoma [15,21] and sonic hedgehog-subtype medulloblastoma [22] have been associated with germline TP53 mutations.…”

Genotype Versus Phenotype: The Yin and Yang of Germline TP53 Mutations in Li-Fraumeni Syndrome

“…Recent reports reveal that this mutation now also predisposes to choroid plexus carcinoma 24 and to breast cancer, where its prevalence is as high as 12.1% in Brazilian women who present before the age of 45 years. However, it must be recognized that there is a wide range in the age of onset of cancers in individuals with LFS, regardless of the underlying TP53 mutation.…”