**Genomic Copy Number Alterations in Serous Ovarian Cancer Cancer**

**Genomic Copy Number Alterations in Serous Ovarian** 

DOI: 10.5772/intechopen.72695

Joe R. Delaney and Dwayne G. Stupack

[160] Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Current

[161] Kandalaft LE et al. Immunotherapy for ovarian cancer: what's next? Journal of Clinical

[162] De Felice F et al. Immunotherapy of ovarian cancer: The role of checkpoint inhibitors.

[163] Zand B, Coleman RL, Sood AK. Targeting angiogenesis in gynecologic cancers. Hema-

[164] Chester C et al. Immunotherapeutic approaches to ovarian cancer treatment. Journal of

[165] Alvarez RD et al. A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: A gynecologic oncology

[166] Marchetti C et al. Targeted drug delivery via folate receptors in recurrent ovarian can-

tology/Oncology Clinics of North America. 2012;**26**(3):543-563 viii

Biology. 2014;**24**(10):R453-R462

110 Ovarian Cancer - From Pathogenesis to Treatment

Oncology. 2011;**29**(7):925-933

Immunotherapy Cancer. 2015;**3**:7

Journal of Immunology Research. 2015;**2015**:191832

group study. Gynecologic Oncology. 2014;**133**(3):433-438

cer: A review. Oncology Targets Therapy. 2014;**7**:1223-1236

Joe R. Delaney and Dwayne G. Stupack Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72695

#### **Abstract**

Precision medicine in cancer is the idea that the recognition and targeting of key genetic drivers of a patient's tumor can permit more effective and less toxic outcomes. Point mutations that alter protein function have been primary targets. Yet in ovarian cancer, unique genetic mutations have been identified only in adult granulosa cell tumors, with a number of other point mutations present in mucinous, clear cell and endometrioid carcinoma subtypes. By contrast, the serous subtype of ovarian cancer shows many fewer point mutations but cascading defects in DNA damage repair that leads to a network of gains and losses of entire genes called somatic copy number alterations. The shuffling and selection of the thousands of genes in serous ovarian cancer has made it a complex disease to understand, but patterns are beginning to emerge based on our understanding of key cellular protein networks that may provide a better basis for future implementation of precision medicine for this most prevalent subtype of disease.

**Keywords:** SCNA, aneuploidy, autophagy, beclin-1, p53

#### **1. Introduction**

When a patient asks an oncologist what tumor cells are, the frequent explanation is that the "Cancer cells are normal cells that accumulate genetic mutations, which causes them to grow out of control." Yet the idea of what a mutation is, and what it can do, varies. It has essentially become dogma that mutations be grouped into two broad categories. One class has been described as either *drivers*, which are key genetic changes that are known to potentiate tumor development. If a gene is not a driver, then it is typically considered a *passenger*,—a bystander mutation occurring due to the tumor-associated genomic instability. Passenger mutations are generally considered to be 'noise' in the system which do not influence tumor progression [1].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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This categorization has now had clinical impact. Genes that are known as *drivers* are prioritized for diagnostic testing, and have become a focus for "molecular tumor boards" that review patient data in hospitals across the United States. These boards focus foremost on reviewing a molecular profiling of the tumor, rather than on histopathological features. Thus, tumors with similar genetic features may call for similar therapy regardless of whether they originate in the colon, breast or lung. The division of mutation into drivers and passengers fosters an environment where new mutations may be missed, because we are focused on the pre-established clinical screening protocols, because we both profile and act upon well characterized genetic problems. Even when they are reported, their impact may not be appreciated if they have not had a role as a driver assigned to them in prior peer-reviewed study.

ovarian cancer (SOC), a lethal tumor whose '*drivers*' are only beginning to be understood. The tumor suppressor gene *TP53* is mutated in more than 85% of serous ovarian cancer (SOC) cases [2], and disruption of DNA repair proteins is commonly identified. Yet most patients

Genomic Copy Number Alterations in Serous Ovarian Cancer

http://dx.doi.org/10.5772/intechopen.72695

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However, SOC has a further characteristic related to its poor capacity to repair DNA. SOC has the highest ratio of somatic copy number alterations (SCNAs) to SNVs for any major cancer. SCNAs are a broad group of genetic changes that encompass a myriad of short insertions, short deletions, translocations and inversions (**Figure 1**, left panel). SCNAs contribute to the mutational landscape of cancer, expanding the scope of changes beyond the more 'simple'

A gene normally occurs in the human nucleus twice. This normal 2N "dosage" of copy number, which originates from zygote formation, consists of one paternal gene and one maternal gene. SCNAs, which alter this occur in two types: amplifications and deletions. An amplification occurs when a chromosomal region containing a gene is copied. That gene will no longer have the normal 2N copy number, but, depending upon the number of times it is copied, could be 3N, 4N, or in cases of massive amplification, up to 200 N and more. Contrasting with this expansive range, SCNAs that result from deletions most frequently reduce the copy number to 1N. Total gene loss (0N) can occur in rare cases, and is associated with a very small fraction of the overall number of deletions. Nonetheless, these rarer SCNA-derived genotypes will obviously impact function most, since the lack of any gene copy means that the encoded protein cannot be produced. SCNAs are the most common lesions in cancer, occurring much

SCNAs occur via a variety of mechanisms in cancer [3]. Entire chromosomes may be gained/ lost during cell division, generating 3N or 1N copy number status for all genes on the chromosome. This occurs due to failed cell-division checkpoints resulting in chromosome missegregation. In contrast to such gains at the total chromosome level, tiny "focal" SCNAs may alter a single gene (or even part of a gene). The most common example of this is *CDKN2A*, a checkpoint protein which is fully deleted (0N) in 3% of SOC tumors. These focal deletions typically occur during repair of double-stranded DNA (dsDNA) breaks. During the attempted repair, short regions of homology can result in accidental deletion of DNA in between [4]. Focal amplifications occur through unknown mechanisms [5] and can form "double minute" chromosomes containing hundreds of copies of a gene, such as *ERBB2* or *EGFR* [6]. Finally, between the focal alterations and the whole chromosome losses, SCNAs can also encompass large regions of DNA through similar defects in dsDNA break repair. These intermediate sized SCNAs can contain many genes. However, they rarely contribute to a 0N copy numbers (loss on both chromosomes) since the regions affected frequently contain essential genes [7]. Within the Cancer Genome Atlas (TCGA) data sets, the presence of 3N and 1N gene copies dominate the SCNA genomic landscape. This is true across all tumors, including those tumors where SCNAs are highly prevalent, such as SOC [8]. SCNAs are prevalent in SOC. In

SNVs. The impact of this on SOC malignancy will be the focus of this chapter.

bear no SNV that results in oncogene activation.

**2. SCNA overview and incidence**

more commonly than SNVs (**Figure 1**, right panel).

The *driver* assignment comes from a breadth of work that focuses on a type of mutation called a somatic single-nucleotide variant (SNV). Driver SNVs are noted for their critical roles in tumor formation, frequently occur at precise locations within *oncogenes*, and can now be rapidly identified. Notable examples include K-Ras, where mutation of the glycine residue at position 12 (G12) inhibits GTPase activity, leaving the protein in an active, GTP-bound effector state. A second example is phosphoinositide 3′kinase, where mutation of the histidine residue at 1047 (H1047) similarly alters the ability of the protein to regulate activity. The gold standard for such driver mutations is their capacity to facilitate neoplastic disease in murine genetic models, most frequently by providing a dysregulated positive stimulus that drives mitosis and cell survival. Transcription factor mutations, such as the FOXL2 C243W mutation found in all adult type granulosa cell tumors, provide a good example of a key genetic driver.

A second class of drivers involve SNV-mediated inactivation of *tumor suppressor* genes, which act to ameliorate the effects of oncogenes, shunt tumors towards programmed cell death, and maintain the fidelity of DNA replication and repair. Tumor formation requires both oncogenic activation and the disruption of tumor suppressors. Mutation in TS genes do not require the same precision as those in oncogenes; SNV's occur across a swath of locations, any of which may be sufficient to disrupt tumor suppressor function. This chapter will focus on serous

**Figure 1.** (Left) Possible changes in a single chromosome's architecture. One chromosome is shown; each copy of a chromosome can have different SCNA or SNV. (Right) A plot of the major cancers in the TCGA database, showing total genetic lesions (as percentage of genes) vs. the number of SCNA for each SNV. In each case SCNA are more abundant, with serous ovarian cancer (SOC, denoted as OVCA in the green box) bearing the greatest number.

ovarian cancer (SOC), a lethal tumor whose '*drivers*' are only beginning to be understood. The tumor suppressor gene *TP53* is mutated in more than 85% of serous ovarian cancer (SOC) cases [2], and disruption of DNA repair proteins is commonly identified. Yet most patients bear no SNV that results in oncogene activation.

However, SOC has a further characteristic related to its poor capacity to repair DNA. SOC has the highest ratio of somatic copy number alterations (SCNAs) to SNVs for any major cancer. SCNAs are a broad group of genetic changes that encompass a myriad of short insertions, short deletions, translocations and inversions (**Figure 1**, left panel). SCNAs contribute to the mutational landscape of cancer, expanding the scope of changes beyond the more 'simple' SNVs. The impact of this on SOC malignancy will be the focus of this chapter.
