Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens

Evans, D. Gareth; Lalloo, Fiona; Howell, Sacha J.; Verhoef, Senno; Woodward, Emma R.; Howell, Anthony

doi:10.1007/s10549-016-3697-z

Cited by 35 publications

(25 citation statements)

References 25 publications

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“…The more advanced disease stage and TNBC subtype in BRCA1 mutation carriers may be associated with a more aggressive clinicopathological tumor type. These observations are consistent with those from previous studies (21)(22)(23)(24). A study conducted by de Bock et al (25) demonstrated that patients with a CHEK2 mutation were significantly younger than patients without this mutation (49.0 vs. 53.2 years; P=0.03).…”

Section: Discussionsupporting

confidence: 92%

Molecular characteristics of breast cancer according to clinicopathological factors

Huszno

Kołosza

2019

mol clin onc

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The purpose of the present study was to evaluate the correlation between molecular factors such as BRCA1 DNA repair associated (BRCA1), checkpoint kinase 2 (CHEK2) and nucleotide binding oligomerization domain containing 2 (NOD2) gene mutations and clinicopathological factors in patients with breast cancer (BC). Prognostic factors were analyzed in BC patients with confirmed BRCA1 (n=73), CHEK2 (n=51) and NOD2 (n=31) mutations. The control group was selected from BC patients without mutations (n=392). The BRCA-associated cancer cases were significantly more often triple negative compared with sporadic cancer (62% vs. 14%; P=0.0001). Luminal B HER2-positive and HER2-positive non-luminal subtypes were observed more often in the control group (33 and 17%). The luminal A subtype was detected in 53% of CHEK2 mutation carriers and 45% of NOD2 mutation carriers. A lower histological grade was observed significantly more often in patients with CHEK2 mutations in comparison with the control group (88 vs. 69%; P=0.003). Lymph nodes without metastases were reported more frequently in NOD2 mutation carriers (74 vs. 54%; P=0.038), in BRCA1 mutations (73 vs. 54%; P= 0.004) and, although not significantly, in CHEK2 mutation carriers (69 vs. 54%; P=0.071) compared with the control group. In conclusion, BRCA1 mutation was associated with TNBC and the luminal B HER2 (-) subtype. HER2-positive subtypes were characteristic of the control group. CHEK2 and NOD2 mutation carriers had a more favorable profile of prognostic factors.

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Section: Discussionsupporting

confidence: 92%

Molecular characteristics of breast cancer according to clinicopathological factors

Huszno

Kołosza

2019

mol clin onc

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“…Our results also capture this relationship, with statistically significant associations between exposures to both APOBEC signatures and HER2 status in both sky and clouds. The negative correlation between Signature 3 and HER2 is consistent with the observation that while BRCA1 and BRCA2 mutation carriers display homologous recombination repair deficiency, that is the phenotype underlining Signature 3, these patients are typically HER2 negative [16].…”

Section: Evaluation Against Clinical and Demographic Datasupporting

confidence: 84%

“…Surprisingly, we also observed an enrichment in transitions between signatures 18 and 30 suggesting a possible relation between these less understood signatures. Further supporting this relationship, we found that these signatures significantly co-occur in the same patients (P < 2.2⇥10 16 for clouds based on Fisher exact test where signatures with exposure at least 0.01 are considered to be present; co-occurrence is not significant in sky). Previous studies linked a new signature that is very similar to Signature 18 to bialleic deactivation of MUTYH, which is involved in base excision repair in response to oxidative damage [47,43,36].…”

Section: Transition Probabilities Reveal An Association Between Signasupporting

confidence: 57%

Hidden Markov Models Lead to Higher Resolution Maps of Mutation Signature Activity in Cancer

Huang

Sason

Wójtowicz

et al. 2018

Preprint

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Abstract. Knowing the activity of the mutational processes shaping a cancer genome may provide insight into tumorigenesis and personalized therapy. It is thus important to uncover the characteristic signatures of active mutational processes in patients from their patterns of single base substitutions. However, mutational processes do not act uniformly on the genome and are biased by factors such as the genome's chromatin structure or replication origins. These factors may lead to statistical dependencies among neighboring mutations, calling for modeling approaches that can account for such dependencies to better estimate mutational process activities.Here we develop the first sequence-dependent models for mutation signatures. We apply these models to characterize genomic and other factors that influence the activity of previously validated mutation signatures in breast cancer. We find that our tool, SigMa, can accurately assign genomic mutations to mutation signatures, yielding assignments that are of higher likelihood than those obtained with models that assume independence between signatures and align better with current biological knowledge. Our analysis resolves a controversy related to the dependency of APOBEC signatures on replication time and links Signatures 18 and 30 to oxidative damage.Modeling the sequential dependencies of mutation signatures leads to improved estimates of mutation signature activity both at the tumor-level and within specific genomic regions, yielding higher resolution maps of mutation signature activity in cancer.

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“…Accordingly, Luminal B and Her2-enriched molecular subtypes had higher BRCA1 scores than Luminal A and triple negative tumors. Previous studies have reported low HER2 amplification amongst BRCA1 mutation carriers who conceivably have impaired BRCA1 expression and/or function [ 33 ]. These findings might indicate a connection between BRCA1 and Her2 pathways in breast cancer that is similar to what have been shown for BRCA1 and ER except that the mechanistic link between BRCA1 and Her2 is less understood.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays

et al. 2017

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PurposeMutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings.MethodsWe examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software.ResultsBRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001).ConclusionFindings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer.

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Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens

Cited by 35 publications

References 25 publications

Molecular characteristics of breast cancer according to clinicopathological factors

Molecular characteristics of breast cancer according to clinicopathological factors

Hidden Markov Models Lead to Higher Resolution Maps of Mutation Signature Activity in Cancer

BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays

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