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Hepatoblastoma (HB) is the most common primary liver cancer of childhood, accounting for up to 1% of all paediatric malignancies, particularly in the younger child. HB is associated with congenital abnormalities in approximately one-third of patients, suggesting complex genetic and/or epigenetic factors in its pathogenesis. 1,2 In addition to an association with low birth weight, there are several linked genetic diseases including overgrowth syndromes such as Beckwith-Wiedemann syndrome, chromosomally linked conditions (trisomies 2, 8 and 20) and X-linked Simpson-Golabi-Behmel syndrome, type 1 glycogen storage diseases, Li-Fraumeni syndrome, familial adenomatous polyposis (FAP) 3-6 and type 1 neurofibromatosis. 7Familial recurrence of HB is extremely rare outside of associated adenomatous polyposis coli (APC) families, 8 and a causative relationship between HB and interstitial deletions of 5q21.3-q23.3 (the APC gene region) is well known.9 Consequently, offspring of FAP families have a 750 -7 500 times higher risk of developing HB. 10,11 Although 75 -80% of FAP individuals have APC gene mutations, there is a group with non-typical de novo genetic variation.6 As a result, the screening of HB patients for APC gene variation in cases of childhood HB without a family FAP history remains an open discussion. It appears to be important to identify these high-risk individuals and perform long-term screening to improve their management.We aimed to investigate HB-FAP gene associations and clinical implications in a South African population. MethodsBased on available clinical data of 2 known FAP families, a local database of 113 FAP cases (1989113 FAP cases ( -2010 was investigated for HB associations. Data were analysed for details of clinical problem, treatment, complications and management. Long-term morbidity and functional outcome were analysed to identify management difficulties. ResultsHB was evident in the offspring of 3/113 known FAP cases (2.65%). Case 1A 2-year-old child re-presented after absconding half-way through a course of chemotherapy (cisplatinum and doxorubicin (PLADO)) for a stage 4 HB. Lung metastases were excised and a right hemi-hepatectomy of a calcified tumour was performed with removal of an additional localised lesion in the left lobe of the liver (Fig. 1). He has survived into adulthood (22 years) without further HB metastatic events. He presented with rectal bleeding at 14 years of age and a pedunculated adenomatous polyp was identified on colonoscopy and removed. He subsequently developed multiple rectal and colonic polyps, for which a total colectomy was performed. Recurrence of rectal polyps in his rectal stump necessitated revision of the lower rectal stump and fashioning of a pouch. Genetic studies identified an APC gene mutation (exon 6 codon 232 C→T). Further investigation of family history revealed relations to a large well-known FAP mixed-ancestry family with >20 affected patients. Case 2A mixed-ancestry male infant in a family without any FAP history was diagnosed with HB in the l...

Colorectal adenomas are macroscopically visible morphological changes of the mucosa that can develop focal carcinoma in the absence of surgical intervention. The successive molecular changes proposed to occur at different stages in the adenoma-carcinoma sequence were primarily based on DNA studies of exophytic, polypoid-type adenomas. Not all colorectal lesions, however, display an exophytic phenotype and a presumed distinct colorectal neoplasm, the nonpolypoid adenoma, was subsequently described as a precursor of colorectal cancer. The low incidence of KRAS mutations in nonpolypoid colorectal adenomas reported previously suggested a different genetic basis for the transformation process in these lesions. We have pursued the identification of genetic changes in benign sporadic nonpolypoid colorectal adenomas in a selected Swedish patient group with no family history of colorectal cancer. Mutation screening of the adenomatous polyposis coli (APC), KRAS, and TP53 genes was conducted using the protein truncation test, heteroduplex-single-strand conformation polymorphism analysis, and denaturing gradient gel electrophoresis on PCR-amplified fragments. Fourteen mutations in the APC gene were characterized in 10/20 samples. Mutations in the KRAS and TP53 genes were identified in 3/57 and 4/51 adenomas, respectively. The mutation frequencies and distribution of mutations in APC correlate with published data on exophytic adenomas. The low mutation frequency of the TP53 gene is consistent with the benign nature of the research material. KRAS activation (an early event in polypoid colorectal adenomas) apparently does not play a significant role in nonpolypoid adenoma development but may result in the development of a polypoid configuration. Genes Chromosomes Cancer 27:202-208, 2000.