Clinical implications of the molecular relationship between HER2 and BRCA1

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10536-10536 ◽  
Author(s):  
R. E. Ellsworth ◽  
B. Deyarmin ◽  
J. A. Hooke ◽  
C. D. Shriver
Keyword(s):  
Genomic Instability ◽  
Copy Number ◽  
Allelic Imbalance ◽  
Genetic Modifier ◽  
Brca1 Gene ◽  
Breast Tumors ◽  
Her2 Status ◽  
Fish Analysis ◽  
Her2 Amplification ◽  
Chromosome 17Q

10536 Background: While HER2 status is used prognostically, the effects of HER2 can be influenced by other genes; co- amplification of TOP2A modulates the effectiveness of treatment with Herceptin. BRCA1, deleted in >50% of sporadic breast tumors, is located distal to HER2 on chromosome 17q and is marked by structural instability. To determine how alterations at the BRCA1 locus may modify amplification of HER2, FISH analysis of BRCA1 was performed in breast tumors with HER2 amplification and/or allelic imbalance on chromosome 17q12. Methods: HER2 status (n=68) was determined using the PathVysion HER2 kit. For BRCA1 analysis, DNA probes were generated by nick translation from a BAC clone containing the entire BRCA1 gene in conjunction with a CEP 17 probe. Copy number gains and deletions were defined as BRCA1:CEP17 >1.3 and <0.8, respectively; aneusomy was defined when >10% of tumor cells had copy numbers > (polysomy) or < (monosomy) than two. Results: Amplification of the HER2 gene was detected in 57% of tumors; an additional 16% of tumor were polysomic for chromosome 17q. The remaining 27% of tumors had previously detected allelic imbalance at the 17q12 region. The majority of samples (47%) were characterized by an amplification of HER2 with a downstream deletion of BRCA1, while HER2 and BRCA1 were amplified concomitantly in 21% of tumors, including those with polysomy of 17q. Fifteen percent of samples were monosomic for chromosome 17q; using current clinical scoring criteria, each of those samples were reported as having, despite the altered copy number, negative HER2 status. Levels of overall genomic instability, which were previously measured at 26 chromosomal regions, were significantly higher (P<0.05) in tumors with deletion of BRCA1 compared to those without loss of BRCA1 (38% and 24%, respectively). Conclusions: Alterations, especially deletions, of BRCA1 are highly correlated with copy number changes in HER2. Because deletion of BRCA1 has been associated with overall genomic instability, patients with amplification of HER2 and deletion of BRCA1 may prove unresponsive treatment with Herceptin. Loss of BRCA1 should, therefore, be considered as a genetic modifier to HER2 amplification and the status of BRCA1 should be considered in selecting treatment options for patients with HER2 amplified tumors. No significant financial relationships to disclose.

Next-generation sequencing (NGS) identifies a new breast cancer subtype with HER2 low-amplification status as a candidate for targeted therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 553-553
Author(s):  
Guo-Chun Zhang ◽  
Ning Liao ◽  
Bo Chen ◽  
Jiali Lin ◽  
Jianguo Lai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Receiver Operating Curve ◽  
Her2 Status ◽  
Her2 Expression ◽  
Her2 Amplification ◽  
Her2 Positive ◽  
Mutation Profile

553 Background: HER2 expression or amplification qualify patients to receive targeted therapeutics against HER2; however, traditional methods of quantifying HER2 amplification using fluorescence in situ hybridization (FISH) do not include a reliable definition for low level amplification. With the promising response rate of patients with low HER2 amplified-metastatic breast cancer to subsequent-line trastuzumab deruxtecan (DS-8201a) therapy, there is a need to improve the existing criteria to accurately identify patients with low HER2. In our study, we investigate whether HER2 amplification quantified by NGS could provide a method to stratify patients into subgroups. Methods: A total of 774 patients diagnosed with breast cancer from Guangdong Provincial People's Hospital (GDPH) who underwent targeted NGS using 520 or 33 cancer-related genes and had their HER2 status evaluated with either FISH or IHC were included in this study. HER2 status were defined as per 2018 ASCO/ACP guidelines. Results: Our results demonstrate that NGS could quantify HER2 amplification with high sensitivity and specificity, with area under the curve of 0.990 [95%CI: 0.982-0.999]. The receiver operating curve indicated an optimal cut-off of 2.62 copy number (CN) for identifying IHC/FISH HER2-negative status with 97.8% specificity. Meanwhile, the cut-off of ≥ 3.62 CN identified patients with IHC/FISH HER2-positive status with 99.8% specificity. Among the 774 patients, 65.8% (n = 509) had HER2 CN of ≤ 2.62 and were classified as HER2 non-amplified, while 25.8% (n = 199) had HER2 CN of ≥ 3.62, classified as HER2-amplified. The remaining 66 patients (8.5%) had HER2 CN between 2.62 and 3.62, and were the patients with heterogeneous IHC/FISH results, classified using NGS as HER2 low-amplified. Patients with low-amplified (49.0% vs. 38.8%, P < 0.001) and amplified (50.3% vs. 38.8%, P < 0.001) HER2 had significantly more number of copy number amplifications in other gene, including CDK12, RARA, and SPOP (P < 0.001, P < 0.001) than patients with HER2 non-amplified, indicating distinct mutation profile. Conclusions: Our results demonstrate that NGS could provide a more accurate stratification of patients based on their HER2 amplification levels. Patients with low levels of HER2 amplification has a distinct mutation profile, suggesting that NGS could serve as a robust tool to identify patients with HER2 amplification, whether high or low, who could benefit treatment with targeted agents designed against heterogeneous HER2 expression.

Use of CDK6 oncogene amplification and 17q gain to predict poor clinical risk groups in adult medulloblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2030-2030
Author(s):  
S. M. Pfister ◽  
M. Remke ◽  
A. Benner ◽  
W. Werft ◽  
F. Mendrzyk ◽  
...  
Keyword(s):  
Survival Data ◽  
Copy Number ◽  
Prognostic Markers ◽  
Tumor Resection ◽  
Risk Groups ◽  
Adult Patients ◽  
Fish Analysis ◽  
Oncogene Amplification ◽  
Adult Medulloblastoma ◽  
Chromosome 17Q

2030 Background: While in children medulloblastoma comprises the most common malignant brain tumor, it accounts for only 1% of intracranial malignancies in adults. The infrequent appearance of MB in adults poses the question, whether these tumors are the same in adults and children in terms of biological and clinical peculiarities. Methods: Array-CGH was performed for a total 34 adult medulloblastoma samples (>18 years) and results were compared with data from 101 pediatric patients. Selected genomic regions were further investigated by FISH analysis in an independent cohort of 415 samples (112 adult and 303 pediatric). All 146 adult patients received a standard treatment regimen consisting of tumor resection, irradiation of the neuroaxis with 36 Gy, a boost of 20–23 Gy to the posterior fossa, and eight cycles of vincristin, lomustine, and cisplatin. To identify novel prognostic markers, DNA copy-number information was correlated with survival data using log rank and chi-square tests. Results: Copy-number gains of chromosome 17q as well as high-level amplifications of CDK6 were identified as significant adverse prognostic markers in adult medulloblastoma. Apart from one exception, CDK6 amplifications were only observed in adult patients (9% in adults versus 0.2 % in children), whereas amplifications of MYC or MYCN were significantly overrepresented in the pediatric cohort, but when present were also associated with dismal prognosis in adults. Monosomy of chromosome 6, in contrast to the pediatric cohort, was not significantly associated with good prognosis, although nuclear ß-catenin accumulation was detected in most cases (r = 0.68). Based on these results, we propose a molecular staging system for adult medulloblastoma: i) cases with oncogene amplification (10% of cases, 5-year OS = 0%); ii) cases with chromosome 17q gain without oncogene amplification (25% of cases, 5-year-OS = 35%); and iii) cases without oncogene amplification or 17q gain (65% of cases, 5-year OS = 92%). Conclusions: We report on the largest cohort of adult medulloblastoma investigated for genomic imbalances to date. We propose a model for the molecular risk stratification of adult medulloblastoma comprising three distinct genomic risk groups with significantly different survival and tumor biology. No significant financial relationships to disclose.

Clinicopathological Follow-up of Breast DCIS Diagnosed on Biopsies: A Single Institutional Study of 575 Patients

2021 ◽  
pp. 106689692110120
Author(s):  
Mingfei Yan ◽  
Phillip Bomeisl ◽  
Hannah Gilmore ◽  
Aparna Harbhajanka
Keyword(s):  
Lymph Node ◽  
Axillary Lymph Node ◽  
Invasive Carcinoma ◽  
Ductal Carcinoma ◽  
Univariate Analysis ◽  
Her2 Status ◽  
Axillary Lymph ◽  
Her2 Amplification ◽  
Therapeutic Implications ◽  
Microinvasive Carcinoma

Stratifying ductal carcinoma in situ (DCIS) patients into different upgrading risk groups is important in exploiting more precise therapeutic options. Evaluation of estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) status and axillary lymph node metastatic status for DCIS and their upgraded invasive counterparts can also provide diagnostic and therapeutic implications. We retrospectively studied 575 patients with first-time diagnosis of DCIS on biopsies, and followed up their final diagnosis, ER/PR/HER2 status, and axillary lymph node involvement on excisions. As a result, biopsy-diagnosed DCIS had an overall 19.1% risk to be upgraded on subsequent excisions, with 4.7% being upgraded to microinvasive carcinoma (pT1mi) and 14.4% to overt invasive carcinoma (⩾pT1a). Factors significantly associated with higher upgrading risk on multivariate analysis include biopsy guidance by ultrasound ( P <.001), DCIS with suspicious microinvasion ( P < .001), and DCIS diagnosed in left breast ( P = .026). DCIS diagnosed in younger patients (⩽40 years old) or DCIS with high nuclear grade showed higher upgrading risk only on univariate analysis. About 80% ER + /PR + and ER−/PR− DCIS remained the same ER/PR status after being upgraded, and ER + /PR −  DCIS had the highest risk (63.6%) of having HER2 amplification in upgraded invasive carcinoma. For upgraded DCIS, microinvasive carcinoma was more likely to have HER2 amplification (50%) than overt invasive carcinoma (29.5%). Besides, pure DCIS had a low risk of axillary lymph node macrometastasis (0.74%), while the risk increased in DCIS with microinvasion (4.4%) and was highest in overt invasive carcinoma (14.7%). The findings of this study are clinically relevant with respect to criteria that might be used in selecting patients for de-escalation trials.

scholarly journals MixHMM: Inferring Copy Number Variation and Allelic Imbalance Using SNP Arrays and Tumor Samples Mixed with Stromal Cells

PLoS ONE ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. e10909 ◽  
Author(s):  
Zongzhi Liu ◽  
Ao Li ◽  
Vincent Schulz ◽  
Min Chen ◽  
David Tuck
Keyword(s):  
Copy Number Variation ◽  
Stromal Cells ◽  
Copy Number ◽  
Allelic Imbalance ◽  
Snp Arrays ◽  
Number Variation

scholarly journals Detection of HER2 Amplification in Breast Carcinomas: Comparison of Multiplex Ligation-Dependent Probe Amplification (MLPA) and Fluorescence In Situ Hybridization (FISH) combined with Automated Spot Counting

2006 ◽  
Vol 28 (4) ◽  
pp. 151-159
Author(s):  
Elna Moerland ◽  
Rens L. H. P. M. van Hezik ◽  
Toine C. J. M. van der Aa ◽  
Mike W. P. M. van Beek ◽  
Adriaan J. C. van den Brule
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Gene Amplification ◽  
Her2 Status ◽  
Her2 Amplification ◽  
Breast Carcinomas ◽  
Her2 Gene ◽  
Her2 Gene Amplification ◽  
Dependent Probe

In this study the detection of HER2 gene amplification was evaluated using Fluorescence In Situ Hybridization (FISH; PathVysion) in comparison with Multiplex Ligation-dependent Probe Amplification (MLPA), a PCR based technique. These two methods were evaluated on a series of 46 formalin fixed paraffin embedded breast carcinomas, previously tested for protein overexpression by HercepTest (grouped into Hercep 1+, 2+ and 3+). HER2 gene amplification (ratio ≥ 2.0) by FISH was found in 9/10, 10/30 and 0/6 in IHC 3+, 2+ and 1+/0 cases, respectively. Digitalized automated spot counting performed with recently developed CW4000 CytoFISH software was 100% concordant with manual FISH scoring. Using MLPA 18/46 samples showed a clear HER2 amplification. Comparing MLPA and IHC showed the same results as for FISH and IHC. All but one FISH positive cases (18/19) were confirmed by MLPA for the presence of the gene amplification. The overall concordance of detection of Her2 gene amplification by FISH and MLPA was 98% (45/46). Furthermore, both the level of amplification and equivocal results correlated well between both methods. In conclusion, MLPA is a reliable and reproducible technique and can be used as an either alternative or additional test to determine HER2 status in breast carcinomas.

scholarly journals Clinical array-based karyotyping of breast cancer with equivocal HER2 status resolves gene copy number and reveals chromosome 17 complexity

BMC Cancer ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Shelly Gunn ◽  
I-Tien Yeh ◽  
Irina Lytvak ◽  
Budi Tirtorahardjo ◽  
Natasha Dzidic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Chromosome 17 ◽  
Gene Copy ◽  
Her2 Status

scholarly journals HER2 Amplification Status in Feline Mammary Carcinoma: A Tissue Microarray–Fluorescence In Situ Hydridization–Based Study

2018 ◽  
Vol 56 (2) ◽  
pp. 230-238 ◽  
Author(s):  
Luisa Vera Muscatello ◽  
Enrico Di Oto ◽  
Giuseppe Sarli ◽  
Valentina Monti ◽  
Maria Pia Foschini ◽  
...  
Keyword(s):  
Protein Expression ◽  
Gene Amplification ◽  
Her2 Status ◽  
Tyrosine Kinase Receptor ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Her2 Protein ◽  
Mammary Carcinomas ◽  
Her2 Gene Amplification

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor overexpressed in a subset of breast cancer due to HER2 gene amplification. HER2 protein is expressed in feline mammary carcinomas, but little is known about its cytogenetic alterations. The aim of this study was to evaluate HER2 gene amplification status and its correlation with HER2 protein expression in feline mammary carcinomas. Feline mammary carcinomas were retrospectively selected and immunohistochemically (IHC) evaluated for HER2 protein expression. All the HER2 IHC-positive (3+) and equivocal (2+) cases and a subset of negative cases (0/1+) were selected for fluorescence in situ hybridization (FISH). Dual-core tissue microarrays were prepared for FISH. IHC and FISH were evaluated according to the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines. The study included 107 feline mammary carcinomas from 88 queens. HER2 protein expression was positive (3+) in 7 cases (6.5%), equivocal (2+) in 48 cases (45%), and negative (0/1+) in 52 cases (48.5%). HER2 status was indeterminate in 8 feline mammary carcinomas (12%), amplified in 3 (4%), equivocal in 4 (6%), and nonamplified in 53 (78%). HER2 gene amplification and protein expression were significantly positively correlated ( R = 0.283; P < .0001). HER2 gene is amplified in a subset of feline mammary carcinomas despite the HER2 positive or equivocal protein expression, but it remains to be determined if the HER2 amplification is a gene alteration that drives mammary tumor carcinogenesis or only a bystander passenger mutation.

scholarly journals Deciphering the Mechanism of Glyphosate Resistance in Amaranthus palmeri by Cytogenomics

2022 ◽  
pp. 1-7
Author(s):  
Dal-Hoe Koo ◽  
Rajendran Sathishraj ◽  
Bernd Friebe ◽  
Bikram S. Gill
Keyword(s):  
Genome Size ◽  
Copy Number ◽  
Fold Increase ◽  
Glyphosate Resistance ◽  
Resistance Mechanisms ◽  
Fish Analysis ◽  
Amaranthus Palmeri ◽  
Artificial Chromosomes ◽  
Genetic Elements ◽  
Meiotic Chromosomes

In agriculture, various chemicals are used to control the weeds. Out of which, glyphosate is an important herbicide invariably used in the cultivation of glyphosate-resistant crops to control weeds. Overuse of glyphosate results in the evolution of glyphosate-resistant weeds. Evolution of glyphosate resistance (GR) in <i>Amaranthus palmeri</i> (AP) is a serious concern in the USA. Investigation of the mechanism of GR in AP identified different resistance mechanisms of which <i>5-enolpyruvylshikimate-3-phosphate synthase</i> (<i>EPSPS</i>) gene amplification is predominant. Molecular analysis of GR AP identified the presence of a 5- to &#x3e;160-fold increase in copies of the <i>EPSPS</i> gene than in a glyphosate-susceptible (GS) population. This increased copy number of the <i>EPSPS</i> gene increased the genome size ranging from 3.5 to 11.8%, depending on the copy number compared to the genome size of GS AP. FISH analysis using a 399-kb <i>EPSPS</i> cassette derived from bacterial artificial chromosomes (BACs) as probes identified that amplified <i>EPSPS</i> copies in GR AP exist in extrachromosomal circular DNA (eccDNA) in addition to the native copy in the chromosome. The <i>EPSPS</i> gene-containing eccDNA having a size of ∼400 kb is termed <i>EPSPS</i>-eccDNA and showed somatic mosacism in size and copy number. <i>EPSPS</i>-eccDNA has a genetic mechanism to tether randomly to mitotic or meiotic chromosomes during cell division or gamete formation and is inherited to daughter cells or progeny generating copy number variation. These eccDNAs are stable genetic elements that can replicate and exist independently. The genomic characterization of the <i>EPSPS</i> locus, along with the flanking regions, identified the presence of a complex array of repeats and mobile genetic elements. The cytogenomics approach in understanding the biology of <i>EPSPS</i>-eccDNA sheds light on various characteristics of <i>EPSPS</i>-eccDNA that favor GR in AP.

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