J Pathol Transl Med.  2023 Nov;57(6):323-331. 10.4132/jptm.2023.10.22.

BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy

• Oh JH
• Sung CO
• Kim HD
• Chun SM
• Kim J

• KMID: 2547930
• DOI: http://doi.org/10.4132/jptm.2023.10.22

Abstract

Background
Homologous recombination defect is an important biomarker of chemotherapy in certain tumor types, and the presence of pathogenic or likely pathogenic mutations involving BRCA1 or BRCA2 (p-BRCA) mutations is the most well-established marker for the homologous recombination defect. Gastric cancer, one of the most prevalent tumor types in Asia, also harbors p-BRCA mutations.
Methods
To investigate the clinical significance of p-BRCA mutations, we analyzed 366 gastric cancer cases through next-generation sequencing. We determined the zygosity of p-BRCA mutations based on the calculated tumor purity through variant allelic fraction patterns and investigated whether the presence of p-BRCA mutations is associated with platinum-based chemotherapy and a certain molecular subtype.
Results
Biallelic p-BRCA mutation was associated with better response to platinum-based chemotherapy than heterozygous p-BRCA mutation or wild type BRCA genes. The biallelic p-BRCA mutations was observed only in the chromosomal instability subtype, while all p-BRCA mutations were heterozygous in microsatellite instability subtype.
Conclusions
In conclusion, patients with gastric cancer harboring biallelic p-BRCA mutations were associated with a good initial response to platinum-based chemotherapy and those tumors were exclusively chromosomal instability subtype. Further investigation for potential association with homologous recombination defect is warranted.

Keyword

Homologous recombination; Gastric neoplasms; Poly(ADP-ribose) polymerase inhibitors; Chromosomal instability; Genes, BRCA2

Figure

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  Fig. 1. Patient selection process. CTx, platinum-based chemotherapy; EBV ISH, Epstein-Barr virus in situ hybridization stain; MSI, microsatellite instability; MSI-H, high microsatellite instability; MSS, microsatellite stable; p-BRCA mutation, pathogenic or likely pathogenic BRCA1 or BRCA2 gene mutation; RECIST, modified Response Evaluation Criteria in Solid Tumors.

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  Fig. 2. Survival rate according to the p-BRCA mutation status. (A) The presence of p-BRCA mutations is not associated with overall survival regardless of LOH of the mutant allele. (B) The presence of p-BRCA mutations is not associated with progression-free survival regardless of LOH of the mutant allele. LOH−, no loss of heterozygosity of p-BRCA mutation; LOH+, loss of heterozygosity of p-BRCA mutation; p-BRCA mutation, pathogenic or likely pathogenic BRCA1 or BRCA2 gene mutation.

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  Fig. 3. Details of p-BRCA mutations. (A) Among the p-BRCA mutations detected in gastric cancers of 65 patients, 39% show loss of heterozygosity of the mutant allele (LOH+). (B) The detected p-BRCA mutations are scattered throughout the entire exonic area without major hotspots. (C) The variant allelic fractions of p-BRCA mutations with loss of heterozygosity are significantly higher than those of p-BRCA mutations without LOH (p < .001). p-BRCA mutation, pathogenic or likely pathogenic BRCA1 or BRCA2 gene mutation.

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  Fig. 4. Genomic landscape of selected gastric cancer samples. (A) The most frequently mutated genes include TP53, ARID1A, and CDH1. BRCA2 mutations are far more frequent than BRCA1 mutations. (B) All gastric cancers harboring p-BRCA mutations plus LOH of the mutant allele are MSS while most cases harboring heterozygous p-BRCA mutations are MSI-H. p-BRCA mutation, pathogenic or likely pathogenic BRCA1 or BRCA2 gene mutation; LOH, loss of heterozygosity; MSS, microsatellite stable; MSI-H, high microsatellite instability; TMB, tumor mutation burden.

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  Fig. 5. Comparison of copy number and tumor mutation burden. (A) Copy number alteration fraction is significantly higher in p-BRCA mutated group than in BRCA wild-type group. Within p-BRCA mutated group, concomitant LOH is associated with a higher copy number burden. (B) Tumor mutation burden is different depending on p-BRCA mutation and MSI status (Kruskal-Wallis test, p = 3.6e-12). Microsatellite-unstable tumors (MSI-H) are associated with high tumor mutation burdens. Within MSS subgroup, the p-BRCA mutated groups (MSS/LOH+ and MSS/LOH−) are associated with higher tumor mutation burdens than the BRCA wild-type group (Wild) (p = .003 each). The tumor mutation burden is not different according to LOH of the p-BRCA mutant allele (p = .910). (C) Representative copy number plots for tumors with high or low copy number burden are shown. Gastric cancer sample harboring a p-BRCA mutation and a high copy number burden (left) shows multiple segments with copy number gains or losses (indicated by red bars) while the BRCA wild-type tumor (right) does not. p-BRCA mutation, pathogenic or likely pathogenic BRCA1 or BRCA2 gene mutation; LOH, loss of heterozygosity; MSI-H, high microsatellite instability; MSS, microsatellite stable.

Reference

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