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## Meet the editor

Mani T. Valarmathi is currently the Director of Research and Development at Religen Inc., a life science company in Pennsylvania, USA. He began his scientific career as a cancer geneticist, but soon became captivated by the emerging and translational fields of stem cell biology, tissue engineering, and regenerative medicine. After obtaining a bachelor's degree in Chemistry from the University of Madras, Chennai,

Tamil Nadu, India, he obtained an MBBS in Medicine and Surgery and an MD in Pathology from the same university, as well as a Ph.D. in Medical Biotechnology from All-India Institute of Medical Sciences, New Delhi, India. Over the past two decades, he has had extensive experience in research on various types of stem cells, and his research work has been focused on creating bioengineered human 3D vascularized tissue constructs for implantation purposes. At present, much of his research is directed toward developing innovative molecular genetic testing for precision and genetic medicine. He is a member of many prestigious national and international professional societies and scientific organizations, including the International Society for Stem Cell Research (ISSCR), Tissue Engineering and Regenerative Medicine International Society (TERMIS), American Association for Cancer Research (AACR), American Society for Investigative Pathology (ASIP), American Society for Clinical Pathology (ASCP), American Chemical Society (ACS), European Society of Cardiology (ESC), International Society for Heart Research (ISHR), American Society of Gene & Cell Therapy (ASGCT), and American Heart Association (AHA).

### Contents



## Preface

Worldwide, breast cancer is the most common cancer among women, impacting more than 2 million women each year. It is the most common non-skin malignancy in women and the second leading cause of cancer death in women after lung cancer. Ovarian cancer is the eighth most commonly occurring cancer in women. The incidence of breast cancer varies greatly around the world, with more than 2.26 million new diagnoses made annually.

In Western societies, one in eight women is prone to develop breast cancer at some time in her life and some 15% to 20% of women with breast cancer have a positive family history of the disorder. Thus, it is expected that many families will experience more than one case because shared familial risk factors, for example, genes and environment, cause a greater incidence of cancer. Up to 20% of affected women have an affected first- or second-degree relative. Conceivably, many of these represent chance coincidences, but statistical analysis reveals that in 5% to 10% of women with breast cancer the condition is truly familial.

Mutations in the *BRCA1/2* genes are the most common cause of hereditary breast and ovarian cancer (HBOC), and HBOC is an autosomal dominant cancer predisposition syndrome. Individuals with HBOC have a high risk for breast and ovarian cancers and a moderate risk for other cancers, such as prostate, pancreatic, melanoma, and fallopian tube cancers. Nevertheless, not all individuals who inherit a mutation in *BRCA1/2* genes will eventually develop cancer (due to *reduced penetrance*), and the signs and symptoms, type, and age of cancer will also vary within families (due to *variable expressivity*).

Since both *BRCA1* and *BRCA2* genes have very large coding sequences and cancer susceptibility is a result of loss of function, the occurrence of pathogenic mutations might be anywhere in either one (*BRCA1* or *BRCA2*). As a result, genetic testing for *BRCA1/2* mutations is challenging and generally confined to individuals with a demonstrable strong family history or those belonging to certain high-risk ethnicity, for example, Ashkenazi Jewish and Icelandic, permitting easy DNA screening.

Two decades ago, my own doctoral research at the All-India Institute of Medical Sciences (AIIMS), New Delhi, resulted in the systematic discovery of numerous novel germline mutations in the *BRCA1* and *BRCA2* genes in Indian breast and/ or breast-ovarian cancer families for the first time. In the Indian population, *BRCA* mutations are distributed throughout the coding sequence with no apparent clustering. Moreover, the study confirmed the strong influence of Ashkenazi Jewish founder mutation 185del AG (c.68\_69delAG) in familial breast and/or ovarian cancer in Southern India. Thus, the identification of these novel mutations and the wider *BRCA* mutational spectrum ultimately led to the development of a mutation

database for its program of *BRCA* genetic diagnostic testing and counseling in the Indian subcontinent. In this respect, I am deeply grateful to Dr. Abhilasha Agarwal for her cooperation and major contribution to the success of this work.

In recent years, there has been substantial development in *BRCA*-associated hereditary breast and/or breast-ovarian cancer research and its clinical applications, for instance, *BRCA* cancer biology and genomics, epidemiology and prevention, early detection and screening, and diagnosis and treatment. In addition, the advent of various emerging technologies, such as stem cell technology, genome editing technology, pharmacogenomics, and personalized medicine, and the knowledge gained from such studies, have not only enhanced our understanding of *BRCA*-associated cancer but also produced novel insights that could lead to the development and deployment of newer clinical/ therapeutic interventions.

In this context, this book consolidates recent advances in *BRCA*-associated cancer biology and therapeutics, covering a broad spectrum of interrelated topics, and disseminates this essential knowledge in a comprehensible way to a scientific and clinical audience as well as patients, caregivers, and drug and device manufactures, especially to support breast cancer product development.

In this context, the ultimate purpose of this book is dispelling the existing classic mysteries of *BRCA* genes, for instance: (1) Why do *BRCA1* and *BRCA2* mutations lead to tumors in such a well-defined subset of human tissues? (2) Are breasts and ovary exposed to higher rates of DNA damage? (3) Do other tissues have a better back-up DNA repair system and, if so, what might that be? (4) Are these tissues less efficient at eliminating *BRCA*-deficient cells, enabling survival mutations to arise and tumors to form? (5) Finally, how can we take advantage of this deficiency in homologous recombination to specifically kill *BRCA*-mutant cells in cancer patients?

Written by leading experts in basic science and clinical care, this book consists of eight chapters over five sections. The **first section** provides an overview of HBOC syndrome. **Chapter 1** emphasizes the current challenges and future perspectives within the context of the advancement of genetic and precision medicine.

The **second section** deals with the history of *BRCA* discovery. **Chapter 2** depicts the initial steps that led to the discovery of *BRCA* genes using both genetic and statistical tools by diverse groups simultaneously, culminating in one of the best examples of how a scientific discovery may change human society for years to come.

The **third section** discusses the current understanding of *BRCA* structure and function. **Chapter 3** synthesizes the pleiotropic biological functions of both *BRCA1/2* genes and how their interactions with many other critical cellular proteins can contribute to various normal and abnormal cellular functions. It also discusses the clinical relevance of *BRCA* genes and how defects caused by *BRCA* gene mutations might be leveraged to develop newer targets for personalized medicine. **Chapter 4** examines *BRCA1*-associated RING domain-1 (*BARD1*) gene structure and its function in physiological and pathophysiological contexts, highlighting the dual function of the *BARD1* gene both as an oncogene and anti-oncogene, but also highlighting the epigenetic effect on *BARD1* gene expression and the biological consequence of it.

The **fourth section** explores *BRCA*-associated cancers, such as ovarian and prostate cancers. **Chapter 5** underscores the significance of *BRCA1/2* mutations in the development of prostate cancer and its increasing clinical significance with respect to metastatic and lethal prostate cancers. It crystallizes the essence of latest findings and the role of *BRCA* genes alterations pertaining to prostate cancer and emphasizes the importance of a detailed understanding of the complex DNA damage repair network in prostate cancer along with other unstable genomic alterations, providing deeper insights into the diverse functions of poly (adenosine diphosphate-ribose) polymerases (PARPs) and other potential contributors of synthetic lethality. C**hapter 6** provides a comprehensive view of the initiation and progression of ovarian cancer and delves deeper into various genetic and non-genetic factors that govern the ovarian epithelial cancers, with special emphasis on personalized medicine. It also examines why despite recent advancement, insights, and elucidation of various molecular mechanisms underpinning ovarian cancer development, advancement of efficacious therapy for ovarian carcinomas has been problematic, especially for the high-grade serous carcinomas.

The **fifth section** focuses on *BRCA* genetic testing, a tool to gain information, and genetic counselling, a process that helps interpret the information and place it in a personal context. **Chapter 7** delineates the prevalence of *BRCA1/2* mutations in Mexico, as well as the diagnostic and prognostic implication of founder mutations of *BRCA* in the Mexican population and its translation impact on routine clinical practice. **Chapter 8** addresses the most critical factors that govern the study of Quality of Life (QoL) in cancer patients, especially pertaining to *BRCA1/2* germline pathogenic variants and their relevance in cancer risk assessment, personalized medicine management, and cancer prevention. In addition, the chapter synthesizes the evolution of the evaluation of the QoL study according to the current needs of patients with *BRCA* mutations.

This book is a valuable resource not only for medical and allied health students but also for researchers, clinical and nurse geneticists, genetic counselors, and physician assistants. This quick reference will benefit anyone desiring thorough knowledge pertaining to recent advances in *BRCA*-related cancer biology and its associated diagnostic and therapeutic challenges.

I would like to thank the staff of IntechOpen who have produced this book so efficiently, particularly Author Service Manager Ana Javor and Commissioning Editor Marija Nezirović for providing excellent support throughout the preparation of this book. They were remarkably patient and persistent. Finally, this book is dedicated to the loving memory of my beloved parents, the light of a lantern.

> **Mani T. Valarmathi, MD, Ph.D.** Clinical Molecular Diagnostic Laboratory, Religen Inc. | A Life Science Company, Plymouth Meeting, Pennsylvania, USA

**1**

Section 1

Hereditary Breast and Ovarian

Cancer Syndrome

Section 1

## Hereditary Breast and Ovarian Cancer Syndrome

#### **Chapter 1**

### Introductory Chapter: The Influence of BRCA1/2 Genes Mutations on Hereditary Breast and Ovarian Cancer Syndrome - Is it in your Genes?

*Mani T. Valarmathi*

#### **1. Introduction**

Worldwide, breast cancer is even now the most common cancer among women, impacting over 2 million women each year, and still causes the maximum number of cancer-related deaths among women. The incidence of breast cancer varies greatly around the world, with over 2.26 million new diagnoses made annually. In 2022, in the United States (US), more than 287,000 women are expected to be newly diagnosed with the invasive breast cancer; in addition, about 51,400 new cases of ductal carcinoma *in situ* (DCIS) will be diagnosed. Overall, nearly 43,000 women are expected to die from the disease. Breast cancer is not only a women's disease, but over 2700 new cases of invasive breast cancer are also expected to be diagnosed in men in 2022, and nearly 500 men are expected to die from it. Moreover, it is estimated that there were more than 168,000 women living with metastatic breast cancer in the US in 2020 (most recent estimate available). Consequently, breast cancer is the most frequent cancer among women in the US, accounting for 31% of newly diagnosed cancers. Ovarian cancer is the eighth among all cancers, and only lung cancer kills more women and is the second most common cancer in women. Thus, invasive cancer of breast is the most common non-skin malignancy in women and is second only to lung cancer as cause of cancer deaths worldwide [1–5].

Breast cancer arises from the sequential accumulation of genetic (mutations or DNA alterations) and epigenetic changes, occurring over a span of years. Like other cancers, breast cancer is clonal proliferations that arise from cells with multiple genetic aberrations, acquisition of which is influenced by hormonal exposure and inherited susceptibility genes. Almost 12% of breast cancers occur due to inheritance of identifiable susceptibility gene or genes. The main known susceptibility genes for familial breast cancer are, for example, *BRCA1* (*BRCA1* DNA repair associated), *BRCA2* (*BRCA2* DNA repair associated), *TP53* (tumor protein p53), *CHEK2* (checkpoint kinase 2), and *PALB2* (partner and localizer of *BRCA2*). They are all tumor suppressor genes that are involved in ensuring the integrity of the genome. They are part of the systems that detect and repair DNA damage, and interact with many other critical cellular proteins, thus preventing the genomic instability. It is likely

that complete inactivation of these tumor suppressor genes leads to loss of function of these proteins, resulting in a mutator phenotype, and consequently heightened propensity to accumulate genetic damage that enhances cancer development [6].

Everyone is at risk of breast cancer, the most important and strongest risk factors are estrogen stimulation (being born female) or age (getting older), and the risk of developing breast cancer is age dependent and increases with age. In the case of a man, the older a man is, the more likely he is to get breast cancer. However, breast cancer is much less common in men than in women. In the US, a woman in the general population has about a 1 in 8 chance (~13%) of being diagnosed during her lifetime. This also means that there is a 7 in 8 chance she will never have the disease. Similarly, a man's lifetime risk of breast cancer is about 1 in 833 (~0.1%). However, it is equally important to remember that the risk is highly dependent on age; for example, the chance of a women being diagnosed during her earlier life (30th year) is less than 1 in 204, whereas the chance of being diagnosed in her later life (70th year) is 1 in 24 [7]. Hence, unfortunately, of all the identified risk factors that can cause breast cancer, age is the major risk factor, the older the woman, the greater her risk [2, 5, 7].

A series of landmark discoveries during 1990 greatly enhanced our understanding of the role of genes in breast cancer. Currently, there exists a common consensus that around 10% of breast cancers arise mainly due to the influence of a disease-causing mutation with which the individual was born. The role of these putative genes that predispose women to breast cancer can be divided into three categories. For example, (i) the first category is a set of genes that so dramatically increase the lifetime risk, which can be presumed as causing an autosomal dominant disorder with "*incomplete penetrance*," that is because not all members harboring the mutation eventually develop the cancer; (ii) the second category is a set of potentially considerable "*low penetrance"* genes that increase the risk, but not to the level that families in which they are found stand out as breast cancer families; and finally, (iii) the third group is a set of "*very rare single-gene disorders*" that includes breast cancer as a feature, which represents for only about 1% of all breast cancers [5–6].

#### **2.** *BRCA1* **and** *BRCA2* **genes**

In 1990, linkage analysis in a large collection of multicase families (studies of early-onset or premenopausal breast cancer) pinpointed a possible susceptibility locus for early-onset or premenopausal breast cancer at chromosome 17q21, eventually leading to identification of the *BRCA1* gene. Since a proportion of families with early-onset breast cancer did not demonstrate linkage to this region, a further round of systematic analysis in *BRCA1*-negative families revealed linkage to chromosome 13q12.3, resulting in the identification of *BRCA2* gene [6].

In western societies since 1 woman in 8 is prone to develop breast cancer at some time in her life, and some 15 to 20% of women with breast cancer have a positive family history of the disorder, it is expected that many families have more than one case—when shared familial risk factors, for example, genes and environment, cause a higher incidence of cancer. Up to 20% of affected women have an affected first- or second-degree relative. Conceivably, many of these represent chance coincidences, but statistical analysis reveals that in 5 to 10% of women with breast cancer the condition is truly familial (hereditary, due to a single-gene mutation). However, in earlier studies using a biased set of families for a *BRCA1/2* mutation carrier, the

#### *Introductory Chapter: The Influence of BRCA1/2 Genes Mutations on Hereditary Breast… DOI: http://dx.doi.org/10.5772/intechopen.108934*

initial estimates of risk have been variously estimated between 60% and 85%. The population-based survey shows lower risk [2, 4–6].

In addition to the risk to the female relative is greater when one or more of the following factors is present that is, at high risk for hereditary breast and ovarian cancer (HBOC): the markers of *BRCA1/2* mutations include the following: (i) a cluster of cases in close female relatives; (ii) cases with unusually early onset (early age [>35–45 years] at presentation, both invasive and DCIS); (iii) bilateral cases (the occurrence of bilateral disease); (iv) families with both breast and ovarian cancers—particularly a feature with *BRCA1* variants (the occurrence of ovarian cancer, epithelial); and (v) cases with male breast cancer—particularly a feature with *BRCA2* variants (a paternal [or close male relative] history of breast cancer). However, none of these features is entirely specific to *BRCA1/2* breast cancer [8–11].

In general, mutations in *BRCA1* and *BRCA2* are responsible for 80–90% of "*single-gene"* familial breast cancers and about 3% of all breast cancers. Penetrance (*the percentage of carriers who develop breast cancer*) varies from 30 to 90% depending upon the specific mutation present. In women, considering the general population, breast and ovarian cancer risks are 1 in 8 (~13%) and 1 in 50 (~2%), respectively, the *BRCA1/2* genes clearly carry a significantly elevated risk. Equally, the risk of breast and prostate cancer in population of men are ~0.1% and ~ 14%, respectively. Mutations in the *BRCA1/2* genes are the most common cause of HBOC, and HBOC is an autosomal dominant cancer predisposition syndrome. Individuals with HBOC have high-risk for breast and ovarian cancers and moderate risk for other cancers, such as prostate, pancreatic, melanoma, and fallopian tube. Nevertheless, not all individuals who inherit a mutation in *BRCA1/2* genes will eventually develop cancer (due to *reduce penetrance*), and the signs and symptoms, type, and age of cancer will vary within families due to *variable expressivity* [1–5].

Pathogenic variants in *BRCA1* and *BRCA2* account for nearly 15% of cases of familial breast cancer. The lifetime risk of developing the disease is 60–90%, in case of carriers of disease-causing *BRCA1* variants, as well as a 40–60% lifetime risk of developing an ovarian cancer. Similarly, the carriers of pathogenic *BRCA2* variants have a 45–85% lifetime risk of developing breast cancer and confer a slightly lower risk of 10–30% for ovarian cancer. In addition, male breast cancer risk is elevated in


*BRCA—Breast cancer susceptibility genes.*

*\*Overall increased lifetime risk but no convincing evidence, BRCA1 carriers may develop early-onset prostate cancer. \*\*Not well defined or no known increased cancer risk.*

#### **Table 1.**

*Lifetime cancer risks (by age 70) for BRCA mutation carriers in comparison to the general population.*

carriers of *BRCA1/2* mutations (7 to 8%), although it is higher in *BRCA2* gene carriers, and the lifetime risk of developing prostate cancer is around 20%, in the case of male *BRCA2* gene carriers (**Table 1**) [5–6].

The remaining known susceptibility genes, such as *TP53* (17p13.1) and *CHEK2* (22q12.1), account for less than 10% of familial breast cancers. Collectively, germline mutations in *TP53* (Li-Fraumeni syndrome) and mutations in *CHEK2* (confers modest, rather than high risk) account for about 8% of breast cancer and are caused by single-gene defects. Besides, *TP53* is the most frequently mutated gene in sporadic breast cancers (non-germline or somatic). The other genes that play a part in hereditary breast cancer, for instance *PALB2,* which is associated with a 30–60% lifetime risk of breast cancer. Most of these genes control checkpoints in the cell cycle and thus could influence cell division; after DNA damage, p53 and *CHEK2* induce cell cycle arrest and either repair their DNA or die by apoptosis, thus playing complex and interrelated roles in maintaining the genomic integrity [6].

Since both *BRCA1* and *BRCA2* genes have very large coding sequences and considering the fact that cancer susceptibility is a result of loss of function, so the occurrence of pathogenic mutations might be anywhere in either one (BRCA1 or BRCA2); as a result, genetic testing for *BRCA1/2* mutations is challenging and generally confined to individuals with a demonstrable strong family history or those belonging to certain high-risk ethnicity, for example, Ashkenazi Jewish and Icelandic. An estimated frequency of about 1 in 40 Ashkenazi Jews carries a *BRCA* mutation, a prevalence about threefold greater than the background. Three founder variants— 185delAG (c.68\_69delAG), 5382insC (c.5266dupC), and 6174delT (c.594delT)—are very frequent in Ashkenazi Jewish population, permitting easy DNA screening. However, negative screen does not exclude other *BRCA* variants or a variant in another high- and/or moderate-risk gene. Similarly, other populations, such as Icelanders, French-Canadians, and Pakistanis, also have their own specific founder mutations [6–11].

#### **3. Concluding remarks and perspectives**

Inherited cancer susceptibility syndromes (ICSS), such as HBOC, are caused by genetic mutations that place patients at an increased risk of developing cancer. These cancer-predisposing syndromes carry a risk of an additional primary tumor (bilateral or multifocal in the case of breast cancer) and clinically appear at a relatively young age compared with sporadic breast cancers. The tumors may occur at a variety of sites in the body; however, in most cases, one type of cancer predominates. The ultimate goal of screening individuals at high risk of familial cancer is either prevention (such as a change in lifestyle or diet) or early detection of cancer. The identification of *BRCA* carriers is important since increased surveillance, drug therapy (chemoprevention), and prophylactic surgery (risk-reducing surgeries, such as mastectomy and/or salpingo-oophorectomy) can reduce cancer-related morbidity and mortality.

*Introductory Chapter: The Influence of BRCA1/2 Genes Mutations on Hereditary Breast… DOI: http://dx.doi.org/10.5772/intechopen.108934*

#### **Author details**

Mani T. Valarmathi Clinical Molecular Diagnostic Laboratory, Religen Inc. – A Life Science Company, Plymouth Meeting, Pennsylvania, USA

\*Address all correspondence to: valarmathi64@hotmail.com

© 2022 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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