Breast Cancer Genetics

Hereditary Breast Cancer

• 5% of breast cancers are hereditary, inherited in a dominant pattern, with early onset and often bilateral.
• Having a sister diagnosed with breast cancer before age 40 increases the risk to 1 in 4.

BRCA1 and BRCA2

• Located at 17q21 and 13q12, respectively.
• Function: double-strand break repair of DNA.
• Tumor suppressor genes.
• Mutations: 45 to 90% of women with a mutation will develop breast cancer, and increase risk of ovarian cancer.
• BRCA1 also increases risk of colon cancer, male breast cancer, and prostate cancer.

Other Mutations in Inherited Breast Cancer

• Faults in TP53 and PTEN are rarer than BRCA1 and BRCA2 mutations.
• TP53 gene normally controls cell division, causing breast cancer as part of Li-Fraumeni syndrome (<1% of all breast cancers).
• Mutations in PTEN cause Cowden syndrome, increasing risk of breast cancer.

Li-Fraumeni Syndrome

• Rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.
• Familial retinoblastoma occurs when a fetus inherits a chromosome 13 with a deleted RB locus.

Two-Hit Hypothesis by Knudson (1971)

• Not mentioned in detail.

DNA Repair Genes

• DNA repair systems correct DNA damage due to environmental mutations and mismatch bases.
• Inherited defects of either system can result in increased frequency of cancer.

Hereditary Cancer Syndromes

• When a cancer occurs as part of a hereditary cancer syndrome, the initial cancer-causing mutation is inherited through the germline and present in every cell of the body.
• Estimated 5% of colorectal and breast cancer arise from an inherited cancer susceptibility gene.

Familial vs. Hereditary Cancer

• Hereditary cancer: apparently autosomal dominant transmission, early age of onset, multiple primary cancers, and clustering of rare cancers.
• Familial cancer: more cases of a specific type(s) of cancer within a family, but no specific pattern of inheritance.

Features Suggesting Inherited Cancer Susceptibility

• Several close relatives with a common cancer.
• Several close relatives with related cancers.
• Two family members with the same rare cancer.
• Unusually early age of onset.
• Bilateral tumors in paired organs.
• Synchronous or successive tumors.
• Tumors in two different organ systems in one individual.

Breast and Ovarian Cancer

• Not mentioned in detail.

Lynch Syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC)

• Caused by mutations in MLH1, MSH2, MSH6, and PMS2 genes, involved in DNA mismatch repair.
• Accounts for 2 to 5% of total colorectal cancers.
• 70 to 90% of people with Lynch syndrome will develop bowel cancer, mostly under the age of 50.
• Increased risk of developing other cancers, including womb and ovarian cancer in women, stomach, small bowel, and gallbladder.

Peutz-Jeghers Syndrome

• Linked to a mutation in STK11, inherited in an autosomal dominant pattern.
• Increases the risk of bowel cancer and other types of cancer.
• Patients with this syndrome also have melanin spots on lips and perioral regions.

Melanoma

• Caused by too much exposure to ultraviolet light, from sunlight or artificial sources.
• About 1 in 10 people (10%) with melanoma have a strong family history of the disease.

Familial Atypical Multiple Mole Melanoma Syndrome

• Increases the risk of developing melanoma.
• Characterized by more than 50 moles and at least one close relative with a melanoma diagnosis.
• Some families with FAMMM are also at a higher risk of developing pancreatic cancer.

CDKN2A

• Linked to familial cases of melanoma.
• Participates in cell cycle regulation.
• Its mutations are inherited in an autosomal dominant pattern.