Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia

Abstract

Heterozygous germ-line variants of DNA mismatch repair (MMR) genes predispose individuals to hereditary non-polyposis colorectal cancer. Several independent reports have shown that individuals constitutionally homozygous for MMR allelic variants develop early onset hematological malignancies often associated to features of neurofibromatosis type 1 (NF1) syndrome. The genetic mechanism of NF1 associated to MMR gene deficiency is not fully known. We report here that a child with this form of NF1 displays a heterozygous NF1 gene mutation (c.3721C>T), in addition to a homozygous MLH1 gene mutation (c.676C>T) leading to a truncated MLH1 protein (p.R226X). The parents did not display NF1 features nor the NF1 mutation. This new NF1 gene mutation is recurrent and predicts a truncated neurofibromin (p.R1241X) lacking its GTPase activating function, as well as all C-terminally located functional domains. Our findings suggest that NF1 disease observed in individuals homozygous for deleterious MMR variants may be due to a concomitant NF1 gene mutation. The presence of both homozygous MLH1 and heterozygous NF1 mutation in the child studied here also provides a mechanistic explanation for early onset malignancies that are observed in affected individuals. It also provides a model for cooperation between genetic alterations in human carcinogenesis.

Constitutional mismatch repair-deficiency syndrome

“…It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development. The identification of a truncating NF1 mutation in the blood of one patient 16 and data supporting the notion that the NF1 gene is a mutational target of MMR deficiency 17 are in line with this assumption. However, extensive mutation analysis in other CMMR-D patients has not confirmed this theory (see 8,12,18 and papers cited therein).…”

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome

“…37 Signs of NF1 in CMMR-D patients are thought to result from somatic mutations present in a segmental or mosaic status. 38,39 Similarly, it is possible that early embryonic somatic mutations (presumed to occur more frequently in CMMR-D patients) in one or more of the genes implicated in the callosal development are responsible for the occurrence of isolated, largely asymptomatic ACC with or without gray matter heterotopia in CMMR-D patients.…”

Differential MSH2 promoter methylation in blood cells of Neurofibromatosis type 1 (NF1) patients

“…17,18 From these findings, it can be speculated that early or constitutional alterations of mismatch repair genes in NF1 patients may lead to an altered mismatch repair gene expression, and thus to an accumulation of second hits of the NF1 gene being prone to mutation and showing one of the highest mutation rates known for human genes. Interestingly, beside one very recent report, 19 constitutional mutations in human mismatch repair genes could not yet be detected in NF1 patients. 8,16,18,19 DNA methylation as an epigenetic modification of CpG dinucleotides is known to modulate gene transcription.…”

“…Interestingly, beside one very recent report, 19 constitutional mutations in human mismatch repair genes could not yet be detected in NF1 patients. 8,16,18,19 DNA methylation as an epigenetic modification of CpG dinucleotides is known to modulate gene transcription. CpG methylation can cause transcriptional silencing of many tumor suppressor genes.…”

“…[21][22][23] Mismatch repair deficiency is considered to be a modifier in NF1, but constitutional mutations of mismatch repair genes in NF1 patients seem to be very rare. 19 Therefore, methylation may be speculated to be a mechanism explaining reduced mismatch repair activity in NF1 patients with a high tumor burden. This would represent an important modifying factor for NF1 phenotypic severity.…”