Patients with familial adenomatous polyposis (FAP) have increased risk of hepatoblastoma (HB). We report monozygotic twins with HB in a FAP family. To explore genetic alterations in the HBs of the twins, we carried out whole exome sequencing (WES), RNA-seq, and immunohistochemical analyses of the tumors. Additional multiregional digital PCR was performed to profile clonality of each tumor. To determine a pathogenic germline variant in APC, Sanger sequencing was applied for the twins, the father, and the siblings of the father. A pathogenic variant of the APC gene was identified in the father as well as the twins. The WES of the HBs in the twins identified somatic mutations, including an NRAS mutation in the tumor of the first infant (C1), and an ACVR2A mutation in the tumor of the second infant (C2). No somatic mutations were identified in the genes associated with the Wnt signaling pathway. However, accumulation of β-catenin was found in the C1 and C2 tumors by immunohistochemical staining, suggesting activation of the Wnt signaling pathway. Digital PCR analysis revealed that the NRAS mutation was found in multiregional specimens of C1 and those of C2. The ACVR2A mutation was found in multiregional specimens of C2, whereas the mutation was also identified in those of C1. The existence of a shared somatic mutation may suggest that microchimerism took place in the development of HBs through the utero-placental circulatory system. Importantly, the initiation of tumorigenesis is thought to occur during the fetal period after organ development of the liver.

Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1) has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations in CDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F). BAP1 missense variants occurred in 0.63% of cases but no CDK4 variants were observed in the sample. This is the first estimate of the contribution of BAP1 and CDK4 to a population-based sample of CMM and supports the previously reported estimate of CDKN2A germline mutation prevalence.

Five to ten per cent of all breast cancers are associated with a proven genetic predisposition for the disease or a strong family history of breast cancer in which yet unknown genetic predisposition is suspected. Carriers of germline mutations in genes breast cancer 1 or 2 (BRCA1/2) have up to 85% chance of developing breast cancer during their lifetime. The majority of these women develop the disease before the age of 50 years. Consequently, breast-cancer screening programmes aimed at reducing mortality in this population may only be effective if they start at much younger age than the general breast-cancer screening programmes. Unfortunately, the efficacy of conventional X-ray mammography in premenopausal women is often limited by dense fibroglandular tissue that obscures suspicious lesions. As a result, more advanced breast-imaging techniques have been considered, such as contrast-enhanced (CE) magnetic resonance imaging (MRI). In symptomatic patients, the sensitivity of CE MRI to detect invasive breast cancer is known to be high, regardless of the density of the fibroglandular tissue. Conversely, the specificity of CE MRI to discriminate between benign and malignant lesions is variable, and depends on the indication of the examination. Low specificity could result in many recalls on benign lesions, thus negatively affecting the cost–benefit ratio of CE MRI as a screening technique. Several single- and multi-institutional studies have been performed to investigate the efficacy of CE MRI as a screening tool exclusively for asymptomatic women at increased lifetime risk of breast cancer. Mounting evidence suggests that the addition of CE MRI results in cost-effective detection of tumours at earlier stage in BRCA1/2 mutation carriers. The value of CE MRI in other populations at risk is currently uncertain, and it is unlikely that CE MRI will be cost efficient in the general screening population of women who are not at increased lifetime risk.