Breast Cancer Genetics - the Implications of Genetic Mutations

Hereditary Breast Cancer:

The Implications of Genetic Mutations

Nicole Kownacki

Felician College

Abstract

The purpose of this paper is to examine the role genetics play related to hereditary breast cancer and the options available for risk reduction and prevention. Four published articles, two medical databases and a genetic focused website were examined during the process of this research. Breast cancer is one of the leading causes of death amongst women and heredity is second only to age amongst risk factors. This paper will show how genetic mutations are linked to hereditary breast cancer and the degree of risk they pose on carriers of these mutations. This paper will also examine the process by which affected individuals should be tested for the mutations, who should be tested and options available for cancer prevention and early detection are available. General statistics regarding the mutations, various preventative actions and screening methods will also be disclosed throughout the course of the paper.

Hereditary Breast Cancer:

The Implications of Genetic Mutations

Documented awareness of breast cancer dates back as far as 1600 BC in Egyptian writings. The idea that breast cancer is linked to heredity was first looked at in the late 1800's. In 1866 a famous French surgeon by the name of Paul Broca came out with the "Broca" report showing that breast cancer can be inherited through families passing from one generation to another (Van der Groep, Van der Wall, & Van Diest, 2011, sec. B). He identified this by constructing a pedigree of his wife's family after she was diagnosed with breast cancer. Presently, a family history of breast cancer is one of the highest risks for developing breast cancer, second only to age. The purpose of this paper is to examine the role genetics play related to hereditary breast cancer and the options available for risk reduction and prevention.

Women with a family history of breast cancer have a significant twofold higher lifetime risk of developing breast cancer than those who do not. Although genetic mutation is a definite factor amongst familial breast cancer, it is not the only link since there are families with breast cancers without germline mutations. According to Isaacs, Fletcher, & Peshkin (2011), "familial cancers may be associated with chance clustering of sporadic cancer cases within families, genetic variation in lower penetrance genes, a shared environment, or a combination of these factors" (sec. 3).

The majority of hereditary breast cancers are linked to two genes, BRCA1 and BRCA2. These genes were first discovered in in 1994 and 1995 respectively and pose a risk of developing breast cancer in women up to 87% by the age of 70 if they carry a mutation in either one of these genes (Metcalf et al., 2007, p. 208). Men who have an abnormal BRCA2 gene are approximately 80 times more likely to develop breast cancer than men who don't, which is about 8% by age 80 ("Genetics," 2012, sec. 2). Hereditary genetic mutations account for approximately 10% of all breast cancer, most commonly being BRCA1 and BRCA2 mutations.

What are BRCA1 and BRCA2 genes and who has them? BRCA1 and BRCA2 are tumor suppressor genes and everyone has them. Since they are tumor suppressor genes they play an important role in maintaining gene integrity, they repair damaged DNA, and serve as checkpoints in cell cycles which allows for repairs to be made before mitosis occurs (Isaacs et al., 2011). The problem and the increased risk for cancer occur when there is a mutation in one or both of these genes. Isaacs et al., (2011) said the following:

Germ line mutations in BRCA1 and BRCA2 result in mutation carriers having loss of one of their wild type alleles and thus they have only one rather than two functional alleles of these genes in their cells. This leads to an increase in genomic instability and tumorigenesis. Tumors in carriers tend to demonstrate loss of the other wild type allele either through loss of heterozygosity or other somatic mutation. The reason why BRCA1 and BRCA2 mutations predispose mainly to breast and ovarian cancers is unclear. At least some data suggest that intact BRCA1 inhibits ligand-independent transcriptional activation of the estrogen receptor-alpha and that functional inactivation could lead to altered hormonal regulation of mammary and ovarian epithelial proliferation (para. 6).

The prevalence of BRCA1 and BRCA2 mutations have been shown to vary in certain geographical areas and ethnic groups, especially among small ancestral groups that may have been geographically or culturally isolated, as seen in the high prevalence of BRCA mutations amongst the Ashkenazi Jewish population (Isaacs, et al., 2011).

The histology of BRCA1 associated breast cancers are associated primarily with invasive ductal adenocarcinomas and have histopathological characteristics including: they are poorly differentiated, have a high mitotic count, show a high frequency of necrotic areas and a remarkable degree of lymphoplasmocytic infiltration and lymphovascular invasion (Van der Groep et al., 2011, sec. 4). Van der Groep (2011) went on to explain that "BRCA1 associated breast cancers are classified as basal and the gene expression profile of BRCA1 tumors involves genes that were found to have functions in proliferation, angiogenesis, cell motility, cell adhesion, transcription and DNA repair" (sec. 4). BRCA1 associated breast cancer has a higher frequency of lung and brain metastasis and a prognosis that studies have found to be similar to worse as compared with sporadic breast cancers in age-matched patients (Van der Groep et al., 2011). The histology of BRCA2 associated breast cancers are associated primarily with invasive ductal carcinomas and are noted to be poorly differentiated with high mitotic rates, increased nuclear pleiomorphism, and have a high proportion of continuous pushing margins (Van der Groep et al., 2011). One main difference between BRCA1 and BRCA2 is that in BRCA1 there is a low expression of the estrogen receptor (ER) and a low expression of the progesterone receptor (PR), and in BRCA2 there is a more frequent expression of ER and PR. According to Van der Groep (2011), "In women with BRCA2 associated breast cancer, bone and soft tissue metastasis are observed more frequently likely associated with their more frequent ER positivity" (sec. 5).

Another genetic mutation that deserves some attention is Li-Fraumeni syndrome, an inherited disorder manifested by a wide range of malignancies occurring with an early age of onset.