BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers

Wang, Guihua; Zhao, Chun‐Mei; Huang, Ying; Wang, Wei; Zhang, Shu; Wang, Xudong

doi:10.1016/j.humpath.2017.10.032

Cited by 34 publications

(40 citation statements)

References 34 publications

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“…In a retrospective study, loss of heterozygosity (LOH) in the BRCA1 locus was associated with decreased DFS and OS [ 43 ]. In another study, high expression of BRCA1 cytoplasmic expression was associated with favorable OS in digestive system cancers [ 44 ]. Our findings are in line with these studies.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

et al. 2018

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BackgroundWe explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC).MethodsIn primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high – low; 412 informative). The primary outcome measure was disease-free survival (DFS).ResultsWe evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively).ConclusionIn non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

et al. 2018

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“…Germline mutations in a single copy of either BRCA1 or BRCA2 can cause hereditary breast and ovarian cancer syndrome, characterized by early-onset breast cancer, as well as increased risks of ovarian, pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. BRCA1 and BRCA2 expression patterns and their prognostic significance in digestive system cancers have been described to be associated with more advanced tumor stage (Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Expression of DNA Damage Response Markers in Early-Onset or Familial Gastric Cancers

Kim

Hwang

et al. 2019

Asian Pac J Cancer Prev

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Background:Early-onset or familial gastric cancer (GC) is known to have clinicopathologic profiles different from those of sporadic GC. We aimed to compare DNA damage response marker expression between early-onset or familial GC and sporadic GC.Methods:GC samples were obtained from patients who underwent gastrectomy for GC at Seoul National University Hospital. Immunohistochemical analyses of various DNA damage response markers, including BRCA1, BRCA2, MRE11, RAD51C, and γH2AX, were performed using 54 early-onset GC, 59 familial GC, and 337 sporadic GC tissue microarray samples. Correlations between marker expression and clinicopathologic features were evaluated by univariate and multivariate analyses, and overall survival was analyzed.Results:The rate of γH2AX positivity was significantly higher (p < 0.001) in early-onset or familial GC than in sporadic GC. In contrast, the rates of MRE11 negativity and RAD51C negativity were significantly higher in sporadic GC than in early-onset or familial GC. BRCA1 negativity was associated with decreased overall survival in sporadic GC (p = 0.002), and MRE11 negativity was associated with decreased overall survival in sporadic GC (p = 0.012).Conclusion:Our results show significant differences in DNA damage response marker expression between early-onset or familial GC and sporadic GC.

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“…However, other studies have performed combined testing for BRCA1/2 mutational screening, along with MMR proteins, while screening for hereditary cancers (35). Other studies have reported IHC detection of BRCA1 in CRC (12,13). A higher proportion of BRCA1 staining in these reports may be due to both cytoplasmic and nuclear staining being considered as positive.…”

Section: Cdx2 Brca1 Mmr Marker --------------------------------------mentioning

confidence: 97%

Identification of colorectal cancers with defective DNA damage repair by immunohistochemical profiling of mismatch repair proteins, CDX2 and BRCA1

et al. 2020

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Colorectal cancer (CRC) is a complex disease as shown by consensus classification. The present study attempted to identify subtypes with known prognostic markers for better clinical management. A total of 72 CRC tumors were examined for the expression of mismatch repair (MMR) proteins, along with caudal-type homeobox protein 2 (CDX2) and BRCA1, by immunohistochemistry. Tumors were assigned based on the presence or loss of MMR proteins as proficient or deficient. Correlations were examined with CDX2 and BRCA1 along with clinico-pathological features. Expressional pattern of microRNAs (miRs/miRNAs), such as miR-183-96-182, known to be associated with defective DNA damage repair were evaluated by reverse transcription-quantitative PCR. A total of 22% of the CRC tumors were assigned as deficient in mismatch repair. 71% of the tumors expressed CDX2 while only 21% had nuclear expression of BRCA1. Loss of CDX2 protein was higher in the deficient subtype compared with the proficient subtype. A total of 14% of the tumors had dual loss of MMR and BRCA1 proteins and showed aggressive clinical features in addition to elevated expression of DNA damage repair microRNAs. The present study shows the presence of a small proportion of colorectal tumors with dual loss of key proteins involved in DNA damage repair which may be amenable to specific therapy. The implication of the present observations warrants investigation in a larger patient cohort with prognostic information.

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BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers

Cited by 34 publications

References 34 publications

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

Expression of DNA Damage Response Markers in Early-Onset or Familial Gastric Cancers

Identification of colorectal cancers with defective DNA damage repair by immunohistochemical profiling of mismatch repair proteins, CDX2 and BRCA1

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