Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer

Abstract

BackgroundConstitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause a hereditary cancer syndrome. This study investigates constitutional promoter methylation as mechanism of inactivation of cancer predisposition genes in genetically unsolved familial and/or early-onset colorectal cancer (CRC) patients.ResultsBisulfite-treated peripheral blood DNA from 46 early-onset/familial CRC patients was analyzed using the Illumina Infinium MethylationEPIC BeadChip. One early-onset CRC patient exhibited constitutional, likely monoallelic, methylation of CpG island 102 in LTBP4, a gene involved in TGF-beta signaling. Somatic methylation of this CpG island is common in CRC, and correlates with LTBP4 downregulation. LTBP4 double knockout mice develop colorectal adenomas and carcinomas, supporting the role of this gene in CRC predisposition. No additional cases with constitutional LTBP4 CpG island 102 methylation or enrichment of deleterious LTBP4 variants in CRC patients compared to controls were found. Another early-onset CRC patient exhibited mosaic BRCA1 promoter methylation, typically associated with increased breast and ovarian cancer risk. No somatic second hit in BRCA1 was detected in the patient's tumor, and homologous recombination deficiency-associated features were inconclusive.ConclusionsOur findings suggest that constitutional methylation of LTBP4 CpG island 102 may be associated with increased CRC risk. Identification of additional cases is needed to confirm the existence of a novel CRC predisposition syndrome driven by epigenetic inactivation of LTBP4, potentially also linked to other clinical phenotypes associated with LTBP4 deficiency, such as pulmonary emphysema. Whether constitutional BRCA1 methylation contributes to CRC risk remains to be determined.