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Cold Spring Harb Mol Case Stud. 2017 Sep 1;3(5). pii: a001628. doi: 10.1101/mcs.a001628. Print 2017 Sep.

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.

Author information

1
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
2
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, British Columbia V5Z 4S6, Canada.
3
Fraser Valley Cancer Centre, British Columbia Cancer Agency, Surrey, British Columbia V3V 1Z2, Canada.
4
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
5
Hereditary Cancer Program, British Columbia Cancer Agency-Abbotsford, Abbotsford, British Columbia V2S 0C2, Canada.
6
British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada.
7
Cancer Genetics Laboratory, Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada.
8
Hereditary Cancer Program, Department of Medical Genetics, British Columbia Cancer Agency, 614-750 West Broadway, Vancouver British Columbia V5Z 1H5, Canada.

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.

KEYWORDS:

neoplasm of the breast; uterine leiomyosarcoma

PMID:
28514723
PMCID:
PMC5593158
DOI:
10.1101/mcs.a001628
[Indexed for MEDLINE]
Free PMC Article

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