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

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, 2, 3, 4, 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 initial estimates of risk have been variously estimated between 60% and 85%. The population-based survey shows lower risk [2, 4, 5, 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, 9, 10, 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, 2, 3, 4, 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 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].

Type of Cancer	Women			Men
	BRCA1 Carrier	BRCA2 Carrier	General Population	BRCA1 Carrier	BRCA2 Carrier	General Population
Breast cancer	60–90%	45–85%	13%	1–5%	7–8%	0.1%
Ovarian cancer	40–60%	10–30%	2%	—	—	—
Prostate cancer	—	—	—	*	~15–25%	14%
Pancreatic cancer	2–3%	3–5%	1%	2–3%	3–5%	1%
Melanoma	**	3–5%	1–2%	**	3–5%	1–2%

Table 1.

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

*

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.

BRCA—Breast cancer susceptibility genes.

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, 7, 8, 9, 10, 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.