Hereditary Cancer

Hereditary Cancer

Family history is a powerful tool for detecting highly penetrant genes responsible for breast cancer susceptibility. This pedigree is very suggestive of a germline mutation due to the presence of multiple affected family members and the development of cancers at a young age. Inheritance can occur through both men and women. Genetic testing could determine if any of the currently recognized mutations are present or establish the significance of a yet undescribed mutation if it consistently maps to individuals with cancer. Some cancers in families (e.g., individual #5 who developed cancer at an older age with an unaffected parent) may be sporadic and not related to an inherited mutation.


Familial Breast Cancer

  • Long recognized that many women with breast cancer also have affected relatives

    • ˜ 10-25% of patients have a 1st-degree relative (parent, sister, daughter) with breast cancer

    • Having affected 1st-degree relative increases patient risk by 2-3x

    • Women whose only family history is mother developing postmenopausal cancer are not at increased risk

      • Majority of postmenopausal breast cancers are sporadic

  • 5-10% of breast cancers have been linked to specific high penetrance germline mutations

    • High penetrance = RR > 10

    • Moderate penetrance = RR 2-3

    • Low penetrance = RR < 1.5

    • Penetrance may be gender dependent for associated cancers (e.g., female carriers are at higher risk for breast cancer than males)

  • Remainder of familial risk is likely due to multiple genes of lower penetrance

    • Unlikely that another highly penetrant gene comparable to BRCA1 or 2 will be identified

Most Common Germline Mutations

  • Majority of germline mutations associated with breast cancer risk are involved in DNA repair pathways

    • Tissue specificity for breast cancers is not understood

    • Mutations are autosomal dominant alleles and thus can be inherited via both females and males

  • BRCA1 (familial breast and ovarian cancer)

    • BRCA1 and 2 help maintain genomic stability

      • Direct role in regulation of DNA-damage responses and repair and cell cycle checkpoints

      • Inactivating mutations impair conservative DNA repair and genomic stability functions

      • Cells lacking BRCA1 & 2 functional activity prone to replication errors and genomic instability

      • Accumulating DNA abnormalities enable mutations in genes essential to cell cycle check point activation

      • Drives acquisition of mutations and chromosomal instability, contributing to tumor formation

    • BRCA1 function is required for transactivation of the estrogen receptor gene promoter

      • May explain why 90% of BRCA1-associated carcinomas are ER(-)

    • Incidence: ˜ 1 in 860

      • More common in some ethnic groups: Ashkenazi Jews, Finns, French Canadians

    • High penetrance: 45-70% lifetime risk

      • Magnitude of risk can vary for different mutations and for different types of cancers

      • Responsible for ˜ 1/2 of cancers known to be due to a germline mutation (˜ 2% of all breast cancers)

    • Other associated cancers

      • Ovarian (40-50% lifetime risk), fallopian tube, peritoneal, and pancreatic cancer

      • Male breast cancer (1-5% lifetime risk, but ˜ 1/2 risk of BRCA2)

    • ˜ 90% of BRCA1 cancers share same gene expression pattern with basal-type carcinomas

      • Basal carcinomas may also have defective BRCA1 function

    • Cancers share morphologic features

      • Mutation can be suspected in young patients (35% risk if grade 3 cancer is ER(-) and patient < 30 years of age)

  • BRCA2 (familial breast and ovarian cancer syndrome)

    • Although BRCA2 is not structurally related to BRCA1, the functions of these genes are very similar

    • Incidence: ˜ 1 in 740

      • More common in some ethnic groups: Ashkenazi Jews, Icelandic populations

    • High penetrance: 40-60% lifetime risk

      • Magnitude of risk can vary for different mutations and for different types of cancers

      • Responsible for ˜ 1/3 of cancers known to be due to a germline mutation (˜ 1% of all breast cancers)

    • Other associated cancers

      • Ovarian (10-20% lifetime risk), fallopian tube, prostate, pancreatic, gallbladder, stomach, bile duct cancers, melanoma

      • Male breast cancer: 5-10% lifetime risk; approximately 5-15% of cases are associated with BRCA2

    • Cancers group with luminal A type by gene expression profiling

  • CDH1 (familial gastric cancer and lobular breast cancer syndrome)

    • CDH1 encodes the gene for E-cadherin

    • Inherited mutations increase risk for signet ring cell carcinomas of stomach and lobular carcinoma

      • Majority of women with lobular carcinomas do not have CDH1 germline mutations

    • 40-85% lifetime risk of developing gastric signet ring cell carcinoma in majority of families

      • Gastric carcinomas are more common than breast carcinomas in most affected families

      • Families developing only breast cancer have also been identified

  • PTEN (Cowden syndrome)

    • Dual specificity phosphatase gene involved in apoptosis

    • Incidence: ˜ 1 in 300,000

    • Characterized by multiple hamartomas (including trichilemmomas)

      • Breast lesions include fibroadenomas and hamartomas

    • Increased risk of breast, thyroid, and endometrial cancer

      • Women have a 25-50% lifetime risk of breast cancer

      • Men also at increased risk for breast cancer

  • TP53 (Li Fraumeni syndrome)

    • P53 has central role in cell cycle control, DNA replication, DNA repair, and apoptosis

    • Increased risk of soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, leukemia, adrenocortical cancer (90% of patients develop some type of tumor by age 70)

      • Breast cancer is 1/3 of malignancies in affected families; found in ˜ 1% of women with breast cancer < age of 40

      • ˜ 55% of women will develop breast cancer by age 45 (average age at diagnosis is 36)

      • Other tumors, particularly sarcomas and brain tumors, can develop in childhood

      • 30% of tumors occur in individuals 15 years of age or younger

    • Somatic P53 mutations are also frequently found in BRCA1 and 2 associated carcinomas

  • ATM (ataxia-telangiectasia carriers)

    • Serine threonine kinase that phosphorylates TP53 and BRCA1 in response to DNA double strand breaks

    • Incidence: 0.2-1%

    • Homozygosity results in ataxia-telangiectasia

      • Progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, and increased risk of leukemia and lymphoma

    • Heterozygosity increases risk of breast cancer

      • 11% by age 50 and 30% by age 70

  • CHEK2 (Li Fraumeni variant syndrome)

    • Cell cycle checkpoint gene involved in DNA repair

    • Incidence: 1 in 100

    • Low penetrance: 10-20% lifetime risk of breast cancer for females and males

  • STK11/LKB1 (Peutz-Jeghers syndrome)

    • Serine/threonine kinase that functions as a tumor suppressor

    • Incidence: 1 in 20,000

    • Characterized by hamartomatous gastrointestinal polyps (including small intestine) and skin pigmentation (lips and buccal mucosa)

    • Increased risk of cancers of colon, breast, stomach, pancreas, small intestine, thyroid, lung, uterus, ovaries, cervix

  • BRIP1 (FANCJ or BACH1)

    • DNA helicase that interacts with BRCA1 to carry out its functions

      • Mutations result in defects in DNA repair

    • Homozygosity results in Fanconi anemia

    • Heterozygosity increases risk of breast cancer

      • Low to moderate penetrance

Patterns of Familial Cancer Likely to be Associated with Germline Mutations

Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hereditary Cancer

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