Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations.

Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.

Germline pathogenic SMARCA4 variants in neuroblastoma.

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4 Median age at diagnosis was 5 years (range 2 months-26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum of SMARCA4-associated tumours.

Five non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype adult patients with m.3243A>G mutation after kidney transplantation: follow-up and review of the literature.

BACKGROUND: Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking. METHODS: We describe five patients with the m.3243AG carriers described in the literature. RESULTS: Proteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation. CONCLUSIONS: Renal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.

Automated measurement of MIB-1 positive area as an alternative to counting in follicular lymphoma.

Manual counting of MIB-1 positive cells which has been suggested as an alternative to centroblast counting for the diagnostic grading of follicular lymphoma is a laborious task. In this study, the validity of automated measurement of the MIB-1 positive area is analyzed as an alternative approach. Archival MIB-1 stained tissue sections of 15 follicular lymphomas were assessed manually and automatically by three independent observers. Concordance correlation coefficients and coefficients of variation were calculated to study reproducibility and variability of both methods and to compare result from both methods. A good concordance was observed between the two methods. The reproducibility of the automated method was slightly better than the manual counting of positive nuclei. Measurement of MIB-1 positive surface area may be used as a simple and fast alternative to tedious manual counting of positive nuclei as a potential help in follicular lymphoma grading.