Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis

AbstractMultiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in theMEN1 gene. The variant (c.654C  >  A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we f ound a likely pathogenic variant in theMLH1 gene (c.27G  >  A), and two risk factor variants in the genesCHEK2 andHOXB13. TheMLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of theMLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without...
Source: Hereditary Cancer in Clinical Practice - Category: Cancer & Oncology Source Type: research