Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germlineCHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma

Abstract

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1. This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.

TAP: a targeted clinical genomics pipeline for detecting transcript variants using RNA-seq data

“…We processed 46 RNA-seq samples of the CBF cohort, of which 26 carry the CBFB - MYH11 fusion (inv(16)), and 20 carry the RUNX1 - RUNX1T1 fusion (t(8;21)). TAP was successful in detecting all of the fusion events, in agreement with the literature [ 30 ]. Two of the CBF - MYH11 cases (03H095 and 12H042) do not have breakpoints at exon boundaries: one presents four extra amino acids at the junction, and the other has a breakpoint internal to the MYH11 exon, both of which nevertheless produce in-frame chimeric transcripts.…”

A Genome-Wide Profiling of Glioma Patients with an IDH1 Mutation Using the Catalogue of Somatic Mutations in Cancer Database

“…Hereditary mutations in CHEK2 have also been shown to predispose patients to multiple cancer types [ 95 ]. In general, mutations in CHEK2 are associated with poor prognosis and reduced patient survival [ 96 , 97 ]. Thus, the decreased frequency of CHEK2 mutations in IDH1-mutant patients improves our understanding of why the IDH1-mutation phenotype is associated with an improved prognosis over IDH1-wildtype.…”