Genetics Of Breast Cancer

Breast Cancer Pathology, Treatment and Genetics

Key Issues • Incidence of breast cancer – Most common breast cancer of women (rare in men but does occur.

• Environmental and inherited risk factors associated with breast cancer. • Pathology of breast cancer (various types). • Treatment • Many genetic changes associated with breast cancer – Multifactorial – Not all changes required for every breast cancer. – Depends of type and nature of cancer

• Difficult to construct a genetic model.

Incidence • Total number cancer in women in 2000 in the UK was 136,153. • 40, 707 of these were breast cancer. • This represents about 30% of all cancers in women. • Breast cancer is the most prevalent of all female cancers. • 1 in 8 women will develop breast cancer during their lifetime. • Of all male cancers (more than 150,000yr) about 250 cases are breast cancer.

Causes of Breast Cancer Environmental • Factors which can increase the lifetime risk are. – – – – – – – – –

Menarche before age 12. Menopause after age 55. First live birth after age 30yrs. Nulliparity. Previous history of breast biopsy. Postmenopausal obesity. Excessive alcohol use. Hormone replacement therapy. Excessive radiation exposure.

• These factors contribute to about a two fold increased risk in the normal population.

Causes of Breast Cancer Heritable • Autosomal dominant syndrome • Cowden Syndrome: associated with mutation in the PTEN gene. 25-50% increased risk. • Peutz-Jeghers Syndrome: Juvenile polyposis syndrome associated with high incidence of breast cancer. – Mutation in STK1 gene (serine-threonine kinase).

• Li-Fraumeni Syndrome: High incidence of many different tumour types – Autosomal dominant mutation in P53 or Chk2 gene.

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Autosomal Recessive

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Bloom Syndrome: Radiation sensitive and cancer prone disorder. Mutation in RecQL3 gene (chr. 15q) – helicase enzyme.

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Werners syndrome: Premature ageing and cancer prone disease. Mutation in RecQL gene (chr. 8p) – helicase enzyme.

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Xeroderma pigmentosum: DNA repair disorder associated with high incidence of skin cancer and also other cancers including breast.

Breast Cancer Types •

Carcinoma in situ: – Confined to the ducts or lobules • Ductal carcinoma in situ. • Lobular carcinoma in situ.

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Infiltrating ductal carcinoma in situ (80% of all breast cancers).

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Infiltrating lobular carcinoma in situ (10-15% of all breast cancers).

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Medullary carcinoma: Invasive but well defined margin between normal and cancer cells (5% of cancers)

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Colloid: Mucinous producing breast cancer Tubular and Adenoid cystic: Very rare breast cancers.

Histology: Normal breast tissue

Pathology

DCIS

Invasive CIS

LCIS

Medullary

Treatment of Breast Cancer Surgery • Breast conservation therapy: Lumpectomy removes only the breast lump and a surrounding margin of normal tissue. • Partial or segmental mastectomy or quadrantectomy removes more breast tissue than a lumpectomy (up to one-quarter of the breast). • Mastectomy: Simple or total mastectomy the – removal of entire breast, but does not remove underarm lymph nodes or muscle tissue from beneath the breast.

• All for early stage breast cancer

Treatment of Breast Cancer Surgery • Radical mastectomy is an extensive operation removing: • Entire breast – Axillary lymph nodes – Pectoral (chest wall) muscles under the breast.

• This surgery was once very common. But disfigurement and side effects are extensive. • Modified radical mastectomy – removal of the entire breast and some of the axillary (underarm) lymph nodes.

Chemotherapy • The most commonly used combinations are: • Cyclophosphamide, methotrexate and 5fluorouracil (CMF) • Cyclophosphamide, Adriamycin 5-fluorouracil (CAF) • Adriamycin and cyclophosphamide (AC) • Adriamycin and cyclophosphamide, Taxol or Taxotere (AC-T). • Adriamycin followed by CMF • Cyclophosphamide, epirubicin and 5-fluorouracil with or without docetaxel. • Every 2 weeks for 4-6 months

Anti-hormonal therapy • Tamoxifen for 5 years or for life depending on stage of tumour. • Radiotherapy may also be used for local disease.

Principle Genes involved in Breast Cancer • Genes associated with breast cancer. – BRCA1 – BRCA2 – P53 – ATM – P65 – PTEN – HER2 family of oncogenes – Cyclin D1

Tumour Suppressor Genes • P53: Mutations of p53 are estimated to occur in up to half of all human cancers and in approximately 20%–30% of breast cancers. •

P27: A member of the P21 family of CDK inhibitors. P27 expression has been shown to have prognostic value in a variety of tumours including breast cancer.

• Reduced expression of p27 is associated with shorter overall survival and shorter time to progression. •

A stronger independent predictor of outcome than either p53 status. –

P27lossmaybeanearlyeventinthedevelopmentofbreastcancer

Tumour Suppressor Genes • Linkage analysis of families with multiple breast cancers, the locus of a gene at 17q21 was reported in 1990. BRCA-1 was subsequently identified in 1994. • About 0.12% of the general population carries a mutation of BRCA-1, but this rate is much higher in certain groups – In Ashkenazi Jews, there is a 1% rate of heterozygosity for the mutation 185delAG and a smaller (0.1%) rate for a separate mutation (5382insC).

• BRCA-1 mutations account for about 5% of all breast cancer cases occurring in women under the age of 40. •

Over 90% for cases families with a history of 4+ cases of breast cancer and more than one case of ovarian cancer

Tumour Suppressor Genes •

Incidence of BRCA-2 heterozygotes in the general population is similar to that for BRCA-1. –

Specific mutation 6174delT occurs at a rate of 1.5% in the Ashkenazi Jewish population. – The Icelandic population carries a separate mutation, 999del5, at a rate of 0.5%. – Present in 40% of cases of male breast cancers.

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Both Brca1 and Brca2 proteins are central to DNA repair processes in the repair of single and double strand DNA breaks. – Non-homologous end joining – Homologous recombination

Tumour Suppressor Genes • PTEN chromosome 10q24, encodes a phosphatase that serves as a negative regulator to Akt signaling. • Loss of PTEN function augments the Akt cell survival signal. Inherited PTEN mutations, seen in Cowden syndrome. – Increases the risk of breast and ovarian cancers – PTEN mutations often seen in advanced breast cancer – late genetic alteration. • Cell cycle checkpoint kinase (CHK2- serine threonine kinase). that is mutated in some families that have a high breast cancer risk - Li-Fraumeni syndrome.

Tumour Suppressor Genes •

The ATM gene senses DNA damage and activates checkpoints and DNA repair pathways through rapid phosphorylation of several substrates. – – – –

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p53, BRCA-1, CHK2. Loss of both alleles of the ATM gene causes ataxiatelangiectasia.

Cancer risk in heterozygotes are variable. – Up to a twelvefold higher risk – Suggests that the risk may be dependent on the type of mutation.

Oncogenes • The HER-2 (human epithelial receptor 2: neu or erbB-2) – Gene is located on chromosome 17q; encodes a 185-kDa transmembrane tyrosine kinase growth factor receptor.

• Mediates signaling via: – (MAP) kinase – (PI3K)/Akt pathways, – Eventuate in proliferation, angiogenesis, altered cell-cell interactions, increased cell motility, metastases, and resistance to apoptosis.

• The HER-2 gene is amplified and overexpressed in 30% of invasive breast cancer and some DCIS (intermediate change). – Heceptin target.

Oncogenes •

Cyclin D1: chromosome 11q13. – overexpressed in 40%–50% of invasive breast cancers (late stage).

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When cyclin D1 is complexed with CDK4/6, pRb is phosphorylated, releasing the transcriptional factor E2F and inducing proteins required for DNA synthesis.

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High cyclin D1 expression level appears to be positively associated an increased proliferative index.

Oncogenes •

The c-myc oncogene: chromosome 8q24 – Encodes a nuclear phosphoprotein that acts as a transcriptional regulator involved in cellular proliferation, differentiation, and apoptosis.

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It is amplified and overexpressed in about 25% of breast cancers – May be associated with a worse prognosis or more aggressive clinical features.

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Myc expression alone is not sufficient for breast carcinogenesis

Summary • Incidence of breast cancer – Most common breast cancer of women (rare in men but does occur.

• Environmental and inherited risk factors associated with breast cancer. • Pathology of breast cancer (various types). • Treatment • Many genetic changes associated with breast cancer – Multifactorial – Not all changes required for every breast cancer. – Depends of type and nature of cancer

• Difficult to construct a genetic model.