An estimated 5%-10% of all breast cancers are believed to have a hereditary component. Most forms of hereditary breast cancer are thought to be part of hereditary breast ovarian cancer syndrome (HBOCS), an autosomal dominant cancer predisposition syndrome in which germline gene mutations in the BRCA1 or BRCA2 gene have a 50-50 chance of being passed from generation to generation. Fewer hereditary breast cancers are believed to be associated with mutations in the TP53, and STK11/LKB1 genes (Mincey 2003).

Additional rarer mutations are seen in the ERBB2 (also called HER2/neu) and the PTEN genes. According to summaries available at the Genetics Home Reference (National Library of Medicine 2008) the ERBB2 (or HER2/neu) and PTEN genes play an important role in cell growth, function, adhesion to neighboring tissue, and movement. Mutations in the ERBB2 (or HER2/neu) gene can lead to unregulated growth and establishment of tumors (25% of all breast cancers and tumors in several other areas of the body have a mutation in this gene). The PTEN gene is a tumor
suppressor gene that normally occurs in many cells all over the body and functions to control cell growth and death cycles (apoptosis is the process of cell decay and death). Mutations in the PTEN gene can mean the absence of these controls and the appearance of cancerous and abnormal non-cancerous cells (uncontrolled cell growth and proliferation). The gene known as p53 is a tumor suppressor with oncogenic properties. Mutations in the p53 gene are thought to occur in over 50% of all human cancers.

The BRCA1 and BRCA2 genes follow the autosomal dominant pattern of inheritance, are present in the germline line (cellular material in ova or sperm that is inherited and can be transmitted to offspring) and play a role in DNA repair mechanisms, cell cycle regulation, and the integrity of the genome (Yarden and Papa 2006). A number of researchers have estimated the risk of development of breast cancer among those with the BRCA1 mutation at 59%-87% and the BRCA2 mutation at 38%-80% (Mincey 2003). Moreover, the risk of ovarian cancer among carriers of the BRCA1 gene ranges from 28% to 44% and that for carriers of the BRCA2 gene ranges from 16% to 27% (Mincey 2003). Those with hereditary cancer, including those who carry the BRCA1 or BRCA2 genes, often demonstrate the onset of disease before the age of 50 (some sources say 45). Other cancers associated with germline mutations in the BRCA1 and BRCA2 genes include pancreatic, early-onset prostate, and laryngeal. It remains unclear whether colon cancer risk is absolutely increased in families who carry BRCA1 or BRCA2 mutations, although mutation carriers are given screening guidelines that manage them at increased risk of colorectal cancer.

Families who demonstrate increased rates of cancer, especially first-degree relatives (parents, children, and siblings), are candidates for further surveillance and possible study of genetic material. An accurate family history covering at least three generations with as much information as possible about ages at onset of illness, medical diagnoses, relevant co-morbidities, causes of death, and related issues is an essential part of health services delivery. A number of models (for example BRCAPRO and Myriad) have been used by specialists in cancer risk assessment to determine the likelihood of the presence of a mutation in the BRCA1 or BRCA2 genes in an individual. These models take into account such variables as the patient’s age and history of breast or ovarian cancer diagnosis, family history of breast cancer, family history of ovarian cancer, family history of men with breast cancer, and ethnic background. While these models help guide clinicians and families in decision making for genetic testing, they are but one type of tool used in making decisions.

Recurring themes in the cancer genetics literature dealing with management of risk assessment include the essential ingredients of genetic counseling, accuracy of cancer diagnoses, and completeness of family and medical histories, when
available. Careful and sensitive handling of preparation for genetic testing, informed consent, and disclosure of genetic testing findings by professionals with training in genetics (including physicians, nurses, and genetic counselors) are paramount. Appropriate referral of patients to specialists is essential. An essential component of genetic risk assessment and counseling includes patients knowing that their genetics providers are there to respond to concerns and support them long after results have been disclosed.

We met Ms. Crandall for the first genetic consultation related to a strong family history of cancer. (See Figure 25-1 on page 381.) Ms. Crandall was diagnosed several months prior to our first visit with a breast cancer at age 38. Surgery was performed with subsequent pathology reports citing a left-sided 2.3 cm infiltrating ductal nuclear grade III, histological grade 2, ER/PR/HER2-negative tumor. Five of 12 axillary nodes were positive for metastasis. The patient was treated with bilateral mastectomy without reconstruction, preferring to wait one year until after completing chemotherapy treatment. Based on information provided to me, I believed that Ms. Crandall (at her relatively young age of cancer onset, still during reproductive years) could be at increased risk of a hereditary cancer syndrome such as Hereditary Breast Ovarian Cancer Syndrome (HBOCS).

Ethnic background: Italian (maternal and paternal)

Sister: Thyroid cancer, not otherwise specified (NOS, meaning that a specific cell type or more detailed description of pathology was not given or available) at age 39

Mother: Ovarian vs. endometrial cancer at age 55, died at age 65

Maternal grandfather: Stomach v. Colon cancer, NOS, died at age 60

Maternal aunt: Breast cancer age 36, died at age 37

The patient and I discussed the information regarding hereditary breast cancer and associated conditions. We reviewed the risks, benefits, and limitations of gene testing, and cancer screening recommendations for Ms. Crandall and her at-risk family members. The patient appeared to have an appropriate understanding of the reviewed information and asked appropriate questions throughout the genetic consultation. Based on the current literature, Ms. Crandall’s probability of having a
BRCA1 or BRCA2 mutation was estimated to be 42.2% (Myriad Genetics 2006). This estimation took into account Ms. Crandall’s personal and family history of breast or ovarian cancer, and her non-Ashkenazi Jewish heritage (the Ashkenazi Jewish population is an ethnic group with increased risks for having BRCA1 and BRCA2 genetic mutations). Based on this estimate, we discussed the option of testing for mutations in the BRCA1 or BRCA2 genes. We also discussed the fact that risk probability models do not outweigh the patient’s personal and family history.

The patient and I reviewed other background information: the BRCA1 and BRCA2 genes are important cancer tumor suppressor genes, and mutations in these genes account for a significant proportion of hereditary breast and ovarian cancer. Cancer-predisposing mutations have been identified throughout the BRCA1 and BRCA2 genes. The current technology for BRCA1 and BRCA2 testing may miss up to 10%-12% of mutations thought to exist within these genes. Therefore, a negative gene test result in a family with a striking family history must be interpreted with caution.

We discussed that there are, most likely, other breast or ovarian cancer syndromerelated genes which exist, but we do not yet have solid research that identifies other genes to test in any given individual or family. Often, variable penetrance factors (conditions that affect the appearance of a disease in persons who posses a given genetic mutation) are at play that are not completely understood now. Also, if we did have additional mutational analysis to offer, this might give Ms. Crandall and her family useful risk information at some future time.

We discussed that everyone is born with two copies of each gene, one from the mother, the other from the father. With tumor suppressor genes and mismatch repair genes, because each person inherits two copies of each gene, it takes two “injuries” to completely disable a gene by disabling both copies. We described that a person who inherits a mutation in a tumor suppressor gene such as BRCA1 or BRCA2 or PTEN is born with one copy of the gene already damaged. Injury to the second copy can greatly increase the risk of cancer. This also explains why hereditary cancer often develops at a younger age than non-hereditary or sporadic cancer. Individuals who are born with inherited risk (a damaged copy) have only one working copy of the gene, which if damaged may set the stage for cancer to develop. In contrast, sporadic cancers tend to develop later in life because both normal, working copies of a gene must become disabled by random mutations. We reviewed the fact
that in true hereditary cancers, the inherited mutation is present in every cell in the body, which is why blood testing can identify the majority of such mutations.