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Case Reports
. 2020 Mar;48(3):300060519886226.
doi: 10.1177/0300060519886226. Epub 2019 Nov 27.

Allele-specific expression mediates primary resistance to poly (ADP-ribose) polymerase inhibitor therapy in a case of BRCA1/2 double-germline mutant gastric cancer

Lu Wen  1 , Xiuxiu Li  1 , Junping Shi  2 , Shuo Zhang  2 , Rui Wang  2 , Ming Yao  2 , Jun Guo  3
Affiliations
Case Reports

Allele-specific expression mediates primary resistance to poly (ADP-ribose) polymerase inhibitor therapy in a case of BRCA1/2 double-germline mutant gastric cancer

Lu Wen et al. J Int Med Res. 2020 Mar.

Abstract

Breast cancer gene 1 and 2 (BRCA1 and BRCA2) are human tumor suppressor genes. BRCA mutations increase the risk for breast, ovarian, and gastric cancer. However, double heterozygosity for BRCA1 and BRCA2 mutations in gastric cancer have not been reported and their clinical significance is unclear. In this study, a 52-year-old Chinese male patient with gastric cancer was chosen for analysis. A tumor tissue biopsy and blood sample were collected, and next-generation sequencing-based deep panel sequencing was performed on the IlluminaNextSeq-500 platform. Comprehensive genomic alterations of 450 cancer-related genes and 47 tumor susceptibility genes were analyzed. Here, we report for the first time a case of gastric cancer that carried both BRCA1 S1841Vfs*2 and BRCA2 Q1886* heterozygous mutations. Unfortunately, the patient was resistant to olaparib treatment. Further RNA analysis revealed that only the wild-type alleles of BRCA1 and BRCA2 were expressed, although genetic BRCA1 and BRCA2 mutations were present in the patient. This genetic finding may explain the mechanism for primary resistance to olaparib observed in the BRCA1/2-mutated patient.

Keywords: BRCA1/2; Gastric cancer; PARP inhibitor; allele specific expression; olaparib; resistance.

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Figures

Figure 1.
Figure 1.
Changes in the solid nodules of the 52-year-old male patient with gastric cancer.
Figure 2.
Figure 2.
Sanger sequencing analysis of the mRNA expression of BRCA1 S1841 (c.5521A) (a) and BRCA2 Q1886 (c.5656C) (b) in the patient’s peripheral blood cells.
Figure 3.
Figure 3.
Family pedigree of the patient.
See this image and copyright information in PMC

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