with hereditary breast cancer.
It is estimated that mutations in RAD51C increase the risk of ovarian cancer by 9% and occur in approximately 1–5.7% of women with ovarian cancer (without considering any selection criteria).
It is estimated that one in 200 people with ovarian cancer will have a constitutional mutation in the RAD51D gene.
When should one suspect a genetic predisposition? The following section outlines the criteria for referral for an oncogenetic consultation, according to the National Comprehensive Cancer Network (NCCN).
1.2.1. Genetic risk assessment criteria1
1.2.1.1. A person with cancer
For a diagnosed patient, the reasons for referral for an oncogenetic consultation, according to the NCCN, are as follows:
1 1) a person with ovarian cancer2;
2 2) a person diagnosed with breast cancer who meets one of the following criteria:– a mutation known in the family in a cancer predisposition gene,– diagnosed with breast cancer at an age ≤ 50 years,– a triple negative breast cancer (ER–, PR–, HER2–) diagnosed at an age ≤ 60 years,– two primary3 breast cancers in a single individual,– breast cancer at any age,– one or more relatives with breast cancer at an age ≤ 50 years,– one or more relatives with invasive ovarian cancer at any age,– two or more relatives4 with breast cancer, prostate cancer (Gleason score > 7 or metastatic) and/or pancreatic cancer at any age,– personal history of pancreatic cancer at any age,– belonging to a population at increased risk5,– male breast cancer;
3 3) an individual with metastatic prostate cancer (radiographic evidence or disease confirmed by biopsy);
4 4) a person of Ashkenazi Jewish descent with breast, ovarian or pancreatic cancer at any age;
5 5) a person with a personal history of one of the following and/or three or more affected family members (especially if diagnosed at ≤ 50 years of age and may include several primary cancers in one person): breast cancer, pancreatic cancer, prostate cancer (Gleason score > 7 or metastatic), melanoma, sarcoma, adrenal cortical carcinoma, brain tumors, leukemia, diffuse gastric cancer6, colon cancer, endometrial cancer, thyroid cancer, kidney cancer, dermatological manifestations7 and/or macrocephaly, or hamartomatous polyps of the gastrointestinal tract8.
DEFINITION.– Macrocephaly refers to an oversized head in infants. It is not a condition in itself, but may be a symptom of other conditions or complications. Macrocephaly is defined as head circumference greater than two standard deviations (SD) above the mean value for a given age and sex.
DEFINITION.– A polyp is a growth protruding from a mucous membrane.
1.2.1.2. Person with no personal history of cancer
An individual with no personal history of cancer, but with:
1 1) a close relative with one of the following:i) a mutation known in the family affecting a cancer predisposition gene,ii) two or more primary breast cancers in the same individual,iii) two or more individuals with primary breast cancers belonging to the same family branch with at least one diagnosed at an age ≤ 50 years,iv) ovarian cancer,v) male breast cancer;
2 2) a first- or second-degree relative with breast cancer at an age ≤ 45;
3 3) a family history of three cases or more of the following (especially if diagnosed at ≤ 50 years of age; may include several primary cancers in the same individual): breast cancer, pancreatic cancer, prostate cancer (Gleason score ≥ 7 or metastatic), melanoma, sarcoma, adrenal cortical carcinoma, brain tumors, leukemia, diffuse gastric cancer, colorectal cancer, endometrial cancer, thyroid cancer, kidney cancer, dermatologic manifestations, and/or macrocephaly, or hamartomatous polyps of the gastrointestinal tract.
DEFINITION.– Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). It can start in a mole (skin melanoma), but can also start in other pigmented tissues, such as the eye or intestines.
DEFINITION.– The term sarcoma generally refers to a broad group of cancers that begin in bone and soft tissue (also called connective tissue) (soft tissue sarcoma). Soft tissue sarcoma forms in the tissues that connect, support and surround other body structures. This includes muscle, fat, blood vessels, nerves, tendons and the lining of joints.
1.3. Indications for genetic testing
The NCCN also now recognizes that multigene panel testing for hereditary forms of cancer can be more efficient and cost effective. It has been shown that 7% of patients with a previously uninformative genetic test had a pathogenic mutation with a multigene panel test.
As such, a thorough family history should not be limited to breast cancer and should include the identification of cancers of other organs that may be part of a breast cancer syndrome or other inherited cancer syndromes.
In patients whose personal or family history suggests more than one hereditary cancer syndrome, or in patients with such a history who have tested negative for a single gene, the NCCN suggests that multigene panel tests should be offered.
NOTE.– Inheriting a BRCA2 or PALB2 mutation from both parents causes specific types of Fanconi anemia. This rare condition is characterized by progressive bone marrow dysfunction, growth delay, variable birth defects, and a high risk of leukemia and early onset solid tumors.
A male or female with a confirmed BRCA2 or PALB2 mutation may therefore consider preconception genetic counseling to clarify the risks in case their partner also carries a mutation in the same gene.
Several organizations have recommended that the BRCA1/2 germline mutation test be offered to all women with epithelial ovarian, tubal or peritoneal cancer, regardless of their histotype, age or family history.
1.4. Tumors
1.4.1. Breast
In terms of histologic types, most breast cancers associated with BRCA1 are of no special type (NST), involving invasive ductal adenocarcinoma and having higher grade than sporadic breast cancers. In terms of molecular subtypes, the majority of BRCA1 breast cancers can therefore be classified as basal-like.
DEFINITION.– Adenocarcinoma is a tumor that begins in glandular (secretory) cells. Glandular cells are found in the tissues that line certain internal organs and produce and release substances in the body, such as mucus, digestive juices, or other fluids. Most of the cancers in the breast, pancreas, lung, prostate and colon are adenocarcinomas.
Like BRCA1-associated tumors and sporadic carcinomas, BRCA2-associated breast cancers are predominantly NST invasive ductal adenocarcinomas with moderate to poor differentiation. However, the overexpression of the estrogen receptor, progesterone receptor, CK8 and CK18 allow BRCA2 tumors to be classified in the luminal molecular subtype, with the vast majority belonging to luminal subtype B.
Most BRCA1 carcinomas have a basal phenotype and are high grade, highly proliferative, estrogen receptor negative and HER2 negative mammary carcinomas characterized by the expression of basal markers such as basal keratins, P-cadherin and epidermal growth factor receptor (EGFR). BRCA1 carcinomas frequently carry p53 mutations.