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Assessment of ERBB2 and TOP2? gene status and expression profile in feline mammary tumors: findings and guidelines.

ABSTRACT: In humans, the ERBB2 gene amplification and overexpression are biomarkers for invasive breast cancer and a therapeutic target. Also, TOP2? gene aberrations predict the response to anthracycline-based adjuvant chemotherapy. Although feline mammary tumors (FMTs) are good models in comparative oncology, scarce data is available regarding the ERBB2 and TOP2? status. In this study, and for the first time, the ERBB2 DNA status and RNA levels of intracellular (ICD) and extracellular (ECD) coding regions were compared with TOP2? gene status and expression profile, in samples of FMTs and disease-free tissues from the same animal. Results showed that ERBB2 and TOP2? gene status are highly correlated (r=0.87, p<0.0001, n=25), with few tumor samples presenting amplification. Also, the majority of the FMTs showed ERBB2 overexpression coupled with TOP2? overexpression (r=0.87, p<0.0001, n=27), being the ERBB2-ICD and ECD transcripts highly correlated (r=0.97, p<0.0001, n=27). Significant associations were found between TOP2? gene status or ERBB2 and TOP2? RNA levels with several clinicopathological parameters. This work highlights the need of experimental designs for a precise evaluation of ERBB2 and TOP2? gene status and its expression in FMTs, to improve their clinical management and to further validate them as a suitable model for comparative oncology studies.

SUBMITTER: Ferreira D

PROVIDER: S-EPMC6660035 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Assessment of ERBB2 and TOP2α gene status and expression profile in feline mammary tumors: findings and guidelines.

Ferreira Daniela D Soares Maria M Correia Jorge J Adega Filomena F Ferreira Fernando F Chaves Raquel R

Aging 20190701 13

In humans, the ERBB2 gene amplification and overexpression are biomarkers for invasive breast cancer and a therapeutic target. Also, TOP2α gene aberrations predict the response to anthracycline-based adjuvant chemotherapy. Although feline mammary tumors (FMTs) are good models in comparative oncology, scarce data is available regarding the ERBB2 and TOP2α status. In this study, and for the first time, the ERBB2 DNA status and RNA levels of intracellular (ICD) an ...[more]

PMID: 31301170

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Project description:IntroductionCancer is a leading cause of death in cats, and the rate of such disease has been increasing recently. Nonetheless, feline oncology represents an important area of study not only for the health and wellbeing of cats but also for human health since various types of cancer in cats share similarities to those found in humans. Therefore, epidemiological studies on feline oncology may suggest environmental and genetic factors contributing to cancer in cats, which can eventually be translated to improve human cancer care.MethodTo provide an initial understanding of the epidemiology of feline neoplasms, a descriptive study was undertaken using a dataset documenting cases of feline cancer gathered from the Liguria region (northwest Italy) spanning from 2002 to 2022. The database includes tumor location, morphological codes of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3), feline's breed, sex, neuter status, date of birth, date of diagnosis, national territorial unit code of the town of the owner's residence, and an alphanumeric string uniquely identifying the owner's surname.Results and discussionThe dataset involves a population of 4,399 cats, including 3,195 females (1,425 neutered) and 1,204 males (750 neutered). Our results indicate that mammary gland tumors are the most represented tumors in the female population, while soft tissue and skin cancers appear to have a higher abundance in the male population during the periods investigated (2002-2022). Moreover, Poisson regression analysis showed that not neutered female cats have a significantly increased risk of developing mammary gland tumors compared to the neutered female population [proportional morbidity ratio (PMR) neutered vs. not neutered = 0.58, 95% CI: 0.47-0.72]; meanwhile, for both sexes, for soft tissue and skin tumors, being neutered appears to be a risk factor (PMR neutered vs. not neutered = 2.26, 95% CI: 1.86-2.73; PMR neutered vs. not neutered = 1.16, 95% CI: 0.89-1.51). Finally, the evaluation of the Ligurian municipalities pollution, based on wild boars data (i.e., biomonitors), which coexisted with cats, was correlated to cancer development for all the tumors investigated (in polluted areas, estimated PMRs ranged from 42.61 to 80.13, 95% CI: 29.94-105.11). Overall, the data presented here suggest the use of the feline population as a possible animal model for human health, i.e., sentinel.

Project description:ImportanceThe 2013/2014 American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) guidelines for HER2 testing by fluorescence in situ hybridization (FISH) designated an "equivocal" category (average HER2 copies per tumor cell ≥4-6 with HER2/CEP17 ratio <2.0) to be resolved as negative or positive by assessments with alternative control probes. Approximately 4% to 12% of all invasive breast cancers are characterized as HER2-equivocal based on FISH.ObjectiveTo evaluate the following hypotheses: (1) genetic loci used as alternative controls are heterozygously deleted in a substantial proportion of breast cancers; (2) use of these loci for assessment of HER2 by FISH leads to false-positive assessments; and (3) these HER2 false-positive breast cancer patients have outcomes that do not differ from clinical outcomes for patients with HER2-negative breast cancer.Design, setting, and participantsWe retrospectively assessed the use of chromosome 17 p-arm and q-arm alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A), as recommended by the 2013/2014 ASCO-CAP guidelines for HER2 testing, in patients whose data were available through Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and whose tissues were available through the Breast Cancer International Research Group clinical trials. We used data from an international cohort database of invasive breast cancers (1980 participants) and international clinical trial of adjuvant chemotherapy in invasive, node-positive breast cancer patients.Main outcomes and measuresThe primary objectives were to (1) assess frequency of heterozygous deletions in chromosome 17 genomic sites used as FISH internal controls for evaluation of HER2 status among HER2-equivocal cancers; (2) characterize impact of using deleted sites for determination of HER2-to-internal-control-gene ratios; (3) assess HER2 protein expression in each subgroup; and (4) compare clinical outcomes for each subgroup.ResultsOf the 1980 patients in METABRIC,1915 patients were fully evaluated. In addition, 100 HER2-equivocal breast cancers by FISH and 100 comparator FISH-negative breast cancers from the BCIRG-005 trial were analyzed. Heterozygous deletions, particularly in specific p-arm sites, were common in both HER2-amplified and HER2-not-amplified breast cancers. Use of alternative control probes from these regions to assess HER2 by FISH in HER2-equivocal as well as HER2-not-amplified breast cancers resulted in high rates of false-positive ratios (HER2-to-alternative control ratio ≥2.0) owing to heterozygous deletions of control p-arm genomic sites used in ratio denominators. Misclassification of HER2 status was observed not only in breast cancers with ASCO-CAP equivocal status but also in breast cancers with an average of fewer than 4.0 HER2 copies per tumor cell when using alternative control probes.Conclusions and relevanceThe indiscriminate use of alternative control probes to calculate HER2 FISH ratios in HER2-equivocal breast cancers may lead to false-positive interpretations of HER2 status resulting from unrecognized heterozygous deletions in 1 or more of these alternative control genomic sites and incorrect HER2 ratio determinations.

Dataset Information

Assessment of ERBB2 and TOP2? gene status and expression profile in feline mammary tumors: findings and guidelines.

Publications

Assessment of <i>ERBB2</i> and <i>TOP2α</i> gene status and expression profile in feline mammary tumors: findings and guidelines.

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