Irina V Kovtun

• Doctor of Philosophy
• Mayo Foundation for Medical Education and Research

Fig. S2. Genome plots showing landscape of structural alterations in donor tumor and PDX tumor.

Fig. S1. IHC staining for HER2 and EGFR proteins in PH026 model.

Fig. S3. IHC staining for HER2 and EGFR proteins in PH048 model.

Fig. S4. Alterations at NRG1 and ERBB2 genes in PH212 model.

Fig. S6. Expression level of NRG1 in ascites detected by qPCR. Immunoblotting for NRG3.

Fig. S5. Immunostaining for NRG1 and HER2 in patient tissues and mouse ascites.

Fig. S7. Expression level of ERBB pathway genes in PH212 model determined by RNAseq.

Data S1. RNAseq supporting reads for gene fusions in PH212 tumors.

Objective: To test the hypothesis that chromosomal rearrangements (CRs) can distinguish low risk of progression (LRP) from intermediate and high risk of progression (IHRP) to prostate cancer (PCa) and if these CRs have the potential to identify men with LRP on needle biopsy that harbor IHRP PCa in the prostate gland. Patients and methods: Mate p...

Ovarian cancer is most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor....

The mechanism of prostate cancer (PCa) progression towards the hormone refractory state remains poorly understood. Treatment options for such patients are limited and present a major clinical challenge. Previously, δ-catenin was reported to promote PCa cell growth in vitro and its increased level is associated with PCa progression in vivo. In this...

Ovarian cancer (OC) is most lethal gynecologic malignancy. About 75% of OC patients relapse and/or develop chemo-resistant disease after initial response to standard-of-care treatment with platinum-based therapies. HER2 amplifications and overexpression in OC are reported to vary and responses to HER2 inhibitors have been feeble. Next generation se...

Purpose: The treatment of ovarian cancer poses a challenge since 70% of patients will relapse with incurable platinum resistant disease. Although ovarian cancers lack frequently-occurring driver mutations or amplifications, the study presented herein examines the concept of individualized therapy based on mate pair sequencing and protein expression...

Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor specifically expressed in 10-20% of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation (NED). ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A⁺AD). RET is a receptor tyrosine kinase with two main human isoforms; R...

Over the recent years significant knowledge has been accumulated on which drugs can be therapeutically beneficial for a given patient based on mutational profiling of their tumors using selected gene panels. Much less, however, is known under which conditions targeting of genes which are amplified could be beneficial. Apart from successfully target...

Recently, the use of a liquid biopsy has shown promise in monitoring tumor burden. While point mutations have been extensively studied, chromosomal rearrangements have demonstrated greater tumor specificity. Such rearrangements can be identified in the tumor and subsequently detected in the plasma of patients using quantitative PCR (qPCR). In this...

Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (...

Circulating tumor DNA (ctDNA) provides great potential for the non-invasive clinical assessment of tumor burden. We developed a monitoring protocol using next generation mate-pair sequencing to identify chromosomal rearrangement signatures in primary tumors to follow ctDNA in blood. Primary tumors of 10 patients with ovarian cancer were sequenced,...

s: AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; June 13-16, 2015; Salt Lake City, UT Ovarian cancer (OCa) is fifth leading cause of death among women. Most of OCa patients diagnosed with high stage invasive disease. Although, majority experience remission after surgical debulking and adjuvant chemotherapy, abou...

Overexpression of TOP2A is associated with risk of systemic progression in prostate cancer patients, and higher levels of TOP2A were found in hormone-resistant cases. To elucidate the mechanism by which high levels of TOP2A contribute to tumor progression we generated TOP2A overexpressing prostate cancer cell lines. We show that TOP2A promotes tumo...

Massive genomic rearrangements, a result of single catastrophic event termed chromothrispsis or chromosomal catastrophe, have been identified in a variety of human cancers. In a few cancer types, chromothripsis was found to be associated with poor prognosis. We performed mate-pair sequencing and analysis of structural rearrangements in 132 prostate...

ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smokin...

Gleason score 7 (GS7) prostate cancer [tumors with both Gleason patterns 3 (GP3) and 4 (GP4)] portends a significantly more aggressive tumor than Gleason score 6 (GS6). It is, therefore, critical to understand the molecular relationship of adjacent GP3 and GP4 tumor cell populations and relate molecular abnormalities to disease progression. To deci...

Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to id...

Over 50% of cancer patients who are treated with epidermal growth factor receptor (EGFR) inhibitors develop a papulopustular rash that involves the face, neck, and upper torso. However, because relatively few previous reports have focused on the full ramifications of this drug-induced side effect, this qualitative study was undertaken. Fifteen pati...

Loss of E-cadherin expression is a critical step in the development and progression of gynecological tumors. Study of the precise role of E-cadherin has been hampered by the lack of satisfactory mouse model for E-cadherin deficiency. Likewise, DNA mismatch repair (MMR) is implicated in gynecological tumorigenesis, but knockout of MMR in mice predom...

OGG1 and MSH2/MSH3 promote CAG repeat expansion at Huntington's disease (HD) locusin vivo during removal of oxidized bases from DNA. CSB, a transcription-coupled repair (TCR) protein, facilitates repair of some of the same oxidative lesions. In vitro, a knock down CSB results in a reduction of transcription-induced deletions at CAG repeat tract. To...

In men who are at high-risk of prostate cancer, progression and death from cancer after radical retropubic prostatectomy (RRP), limited prognostic information is provided by established prognostic features. The objective of this study was to develop a model predictive of outcome in this group of patients. Candidate genes were identified from microa...

Interacting with patients, researchers, and administrators, patient advocates have a unique vantage point. Yet, few prior studies have sought to understand these individuals or to seek their opinions on cancer issues. A survey to address the foregoing was developed and mailed to advocates within the National Cancer Institute's Prostate Cancer SPORE...

Unstable repeats are associated with various types of cancer and have been implicated in more than 40 neurodegenerative disorders. Trinucleotide repeats are located in non-coding and coding regions of the genome. Studies of bacteria, yeast, mice and man have helped to unravel some features of the mechanism of trinucleotide expansion. Looped DNA str...

Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a s...

While a role for DNA glycosylase activity in base excision repair (BER) is well understood, there is mounting evidence to implicate cooperation of DNA glycosylases with components of repair pathways other than BER. The mechanisms by which DNA glycosylases interact with non-BER pathways are, in many cases, poorly understood. However, accumulating ev...

This chapter focuses on repair-dependent models for the expansion at a DNA break. The first and most straightforward mechanism proposed for DNA opening and expansion was polymerase slippage during mitosis. In this model, the polymerase dissociates from the repeat segment on the template strand during DNA synthesis and "slips" back to pair at a prev...

Alterations in trinucleotide repeat length during transmission are important in the pathophysiology of Huntington's disease (HD). However, it is not well understood where, when and by what mechanism expansion occurs. We have followed the fate of CAG repeats during development in mice that can [hHD(-/+)/Msh2(+/+)] or cannot [hHD(-/+)/Msh2(-/-)] expa...

The size of the CAG tract at the Huntington's disease (HD) locus upon transmission depends on the gender of the parent. However, the basis for the parent-of-origin effect is unknown. To test whether expansion and contraction in HD are "imprinted" in the germ cells, we isolated the X- and Y-bearing sperm of HD transgenic mice. Here we show that CAG...

This chapter describes methods for the isolation of specific cell types that reveal how and where expansion can occur. For the hereditary component of expansion, the male germ cell has proved useful in distinguishing processes that can contribute to expansion, as described in our article (Nature Genetics 27, 407, 2001). Mature spermatazoa (SZs) can...

There has been a longstanding debate regarding the role of proteolysis in Huntington's disease. The toxic peptide theory posits that N-terminal cleavage fragments of mutant Huntington's disease protein [mutant huntingtin (mhtt)] enter the nucleus to cause transcriptional dysfunction. However, recent data suggest a second model in which proteolysis...

Huntington disease (HD) is one of eight progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion encoding a polyglutamine tract. The mechanism of trinucleotide expansion is poorly understood. Expansion is mediated by misaligned pairing of repeats and the inappropriate formation of DNA secondary structure as the du...

The mechanism of DNA expansion is not well understood. Recent evidence from genetic, in vivo, and in vitro studies has suggested a link between the formation of alternative DNA secondary structures by trinucleotide repeat tracts and their propensity to undergo expansion. This review will focus on structural features and the mechanism of expansion r...

Gender is known to influence the transmission of trinucleotide repeats in human disease. However, the molecular basis for the parent-of-origin effect associated with trinucleotide repeat expansion is not known. We have followed, during transmission, the fate of the CAG trinucleotide repeat in a transgene containing the exon 1 portion of the human H...

Gender is known to influence the transmission of trinucleotide repeats in human disease. However, the molecular basis for the parent-of-origin effect associated with trinucleotide repeat expansion is not known. We have followed, during transmission, the fate of the CAG trinucleotide repeat in a transgene containing the exon 1 portion of the human H...

Androgen receptors in the liver of pubertal male rats are identified by an indirect immunoperoxidase method. Hepatocyte nuclei predominate among positively stained structures. The intensity of staining varies from hepatocyte to hepatocyte and does not depend on its position in the liver lobule.

Formation of dependence on sex of the unusual estrogen-binding protein (UEBP) expression in rat liver during postnatal development was studied using radioligand and immunohistochemical techniques. UEBP was shown to appear in the male and female liver by day 45 to 50 of postnatal life. In females, UEBP remained at a low level until day 75 to 80, cor...

A possibility of inheritance of androgen and basic genetic programs at the level of unusual estrogen-binding protein (UEBP) by daughter hepatocytes was investigated. Liver regeneration after partial ( ) hepatectomy or after selective poisoning of hepatocytes of the central zone of hepatic lobules with CCl4 in adult rats were used as models of total...

We demonstrate that on the rat liver, testosterone (T) induced differentiated functions and enhanced unusual estrogen-binding protein (UEBP) content through mechanisms dependent on cell activation by androgens, the presence of growth hormone (GH) and the hormonal status of the animal. To determine whether liver cells are a target for androgens, we...

Some features of the formation, expression and inheritance of basic genetic and androgen programs of the level of unusual estrogen-binding protein (UEBP) in mature female rat hepatocytes under experimental conditions were investigated. Liver regeneration after partial (2/3) hepatectomy of mature rats was used for generation of a new population of d...

The content of unusual estrogen-binding protein (UEBP), the level of DNA and common protein as well as the organ mass were studied over time during regeneration of the rat liver of intact males and gonadectomized males and females. In 21 days after partial hepatectomy of males with intact testes complete restoration of the UEBP content was observed...