Cancer Genetics - Breast Anatomy and GYN System

breast anatomy

• 15 - 20 lobes in each breast

• Each lobe has 20 - 40 lobules

  • Lobules are connected via 6 - 8 ducts

    • Ducts connected to lobules carry milk to the nipple

• Shape of the breast maintained by ligaments and connective tissue

  • Nerves throughout the breast provide sensation

• Lymph nodes and blood vessels help fight infection

The Gynecological system

• Ovarian cancer

  • Epithelial ovarian cancer is the most common malignancy

• Primary peritoneal cancer

  • Lining of the abdominal cavity

• Fallopian tube cancer

• Uterine cancer

• Endometrial cancer

Risk factors for breast cancer

Non-Modifiable

• Being female

• Aging

• Ethnicity

• Breast conditions

• Hormone exposure

• Family history

• Inherited mutations

Modifiable

• Obesity

• Alcohol use

• Physical inactivity

• Ionizing radiation exposure

Breast findings

Chemotherapy

• Anticancer drugs used after radiation and surgery

Hormonal therapy

• Tamoxifen

  • treat breast cancer with estrogen and/or progesterone receptors on them

• Aromatase inhibitors

  • Used in the treatment of breast cancer in postmenopausal women and men by stopping and enzyme in fat tissue from changing other hormones into estrogen

Immunotherapy

• Using the body’s own immune system to help fight cancer

PARP inhibitors

• A class of drugs which target cancer cells by exploiting a weakness in their ability to repair DNA damage

  • Useful for cancers with BRCA1/2 mutations (breast, ovarian, prostate, pancreatic)

  • Used in maintenance therapy (to prevent recurrence) and active treatment

• Drugs target the Poly (ADP-Ribose) Polymerase enzymes

  • Enzymes that help repair single-stranded breaks through base excision repair

• Cancer cells with BRCA gene mutations highly depend on PARP enzymes for survival

Lumpectomy

• Removal of the tumor from the breast with radiation

Mastectomy

• Removal of the entire breast or breasts

• May include sentinel lymph node biopsy and axillary lymph node dissection

Risk Factors for Gynecological Cancer

Non-Modifiable

• Aging

• Being female

• Chronic conditions (endometriosis, PCOS, diabetes)

• Hormonal factors (early menarche, late menopause, nulliparity)

• Infertility

• Heredity

Modifiable

• Medications (excess estrogen exposure)

• Obesity

• Smoking

Gynecological tumors

Screening for endometrial / ovarian cancers

• Pelvic exam

• Ultrasound / sonogram

• MRI

• Tumor marker (blood test)

• Biopsy

Surgery for endometrial / ovarian cancers

Surgery

• Hysterectomy (TAH / TH)

  • Removal uterus

    • total abdominal hysterectomy - uterus and cervix removed through abdomen

    • total hysterectomy - removal of uterus and cervix

• Bilateral salpingo-oophorectomy

  • Both fallopian tubes (salpinges) and ovaries are removed

• Lymph node biopsy

• Omental biopsy

  • Tissue sample from the omentum, a fatty apron-like tissue that hangs from the stomach and covers the intestines

• Pelvic washings

  • Flushing the pelvic cavity with a sterile solution to collect fluid and tissue samples for analysis

• Debulking cytoreduction

  • Get all visible cancers out

Non-Surgery treatment options for endometrial / ovarian cancers

Chemotherapy

Radiation therapy

• Endometrial cancer NOT ovarian

Hormonal therapy

• Eg: Progestin

  • Synthetic version of progesterone, present in birth control

  • Prevent pregnancy by inhibiting ovulation

  • Unopposed estrogen can cause an overgrowth of endometrium leading to endometrial cancer

Others

• Immunotherapy

• PARP inhibitors

HBOC Syndromes

• Hereditary breast and ovarian cancer syndromes

• BRCA1 on 17q21.31

• BRCA2 on 17q13.1

• Autosomal dominant

  • Increased risk of breast, ovarian, pancreatic, prostate, melanoma

HBOC Risk vs General

Breast

• BRCA1 = 60 - 70%

• BRCA2 = 55 - 70%

• General = 12 - 13%

Ovarian

• BRCA1 = 39 - 58%

• BRCA2 = 13 - 29%

• General = 1 - 2%

Pancreatic

• BRCA1 = <5%

• BRCA2 = 5 - 10%

• General 1 - 2%

Prostate

• BRCA1 = 7 - 26%

• BRCA2 = 19 - 61%

• General = 12 - 13%

Risk Reduction Options for HBOC

Hormonal therapy

• 50% reduction in breast cancer

Mastectomy

• 90%+ reduction in breast cancer

Bilateral Salpingo-Oopherectomy

• 96% reduction for ovarian cancer

• 50% reduction in breast cancer (in pre-menopausal women)

Oral Contraceptive Pills

• 50% reduction for ovarian cancer (if taken ~10 years)

Cholangiopancreatography (MRCP)

• Pancreas imaging

  • Viewing the bile ducts and the pancreatic duct

  • It can show the pancreas, gallbladder and liver

  • MRCP use MRI to produce detailed pictures of these ducts and organs

Founder mutations in BRCA

• Ashkenazi-Jewish

• Polish

• Norwegian

• Icelandic

PTEN Hamartoma Tumor Syndrome (PHTS)

• PTEN 10q23.3

• KLLN at 10q23.31

• Autosomal dominant

• Increased risk for breast, thyroid, endometrial, colorectal, renal cell, and melanoma cancers

• Can cause many benign tumors

PTEN Hamartoma Tumor Syndrome Phenotypes (PHTS)

• Cowden syndrome (CS)

• Bannyan-Riley-Ruvalcaba syndrome (BRRS)

• Adult L’hermite-Duclos disease

• Protus-like syndrome

• Autism spectrum disorders with macrocephaly

Cowden Syndrome (CS)

• Major criteria

  • Breast cancer

  • Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer

  • Macrocephaly

  • Endometrial carcinoma

• Minor criteria

  • Thyroid lesions (eg. adenoma, multinodular goiter)

  • Intellectual disability

  • Hamartomatous intestinal polyps

  • Fibrocystic disease of the breast

  • Lipomas

  • Fibromas

  • Genitourinary tumors (especially renal cell carcinoma)

  • Genitourinary malformation

  • Uterine fibroids

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

• Congenital disorder characterized by:

  • Macrocephaly,

  • Intestinal hamartomatous polyposis

  • Lipomas

  • Pigmented macules of the glans penis

PTEN-Related Proteus Syndrome

• Highly variable

  • Congenital malformations and hamartomas overgrowth of multiple tissues

  • Connective tissue nevi (mole), epidermal nevi, and hyperostoses

Li-Fraumeni Syndrome

• TP53 at 17p13

• Autosomal dominant

  • 7 - 20% de novo

  • Anticipation

• Very high penetrance

  • Lifetime risk for cancer is >70% for men and >90% for women

• Cancer risks

  • Breast, soft tissue sarcomas, central nervous system cancers, adrenocortical carcinoma, gastrointestinal, hematologic malignancies

• Management

  • Physical exam

  • Whole body MRI

• Suspected when Chrompret criteria

• Diagnostic criteria (All three)

  • Proband with sarcoma diagnosed before 45 years

  • First-degree relative with any cancer before 45 years

  • A first or second degree relative with any cancer diagnosed before 45 years or a sarcoma diagnosed at any age

Li-Fraumeni Clinical Criteria

• Proband with a sarcoma diagnosed before 45 years AND

• First-degree relative with any cancer diagnosed before 45 years AND

• First or second-degree relative with any cancer diagnosed before age 45 or a sarcoma diagnosed at any age

Hereditary Diffuse Gastric Cancer Syndrome

• CDH1 at 16q22.1 (e-cadherin protein)

• CTNNA1 at 5q31.2

• Autosomal dominant

• Established in a proband with diffuse gastric cancer and family history of one or more first- or second-degree relatives with GC OR

• A personal and/or family history of DGC (diffuse gastric cancer) diagnosed before age 40 OR

• Personal and/or family history of DGC and LBC, one diagnosed before 50 years

Genetic testing for CDH1 mutations (hereditary Diffuse Gastric Cancer Syndromes)

• Genetic testing should be ordered

  • Diagnosis of DGC (diffuse gastric cancer) and pathologically confirmed in situ signet ring cells and/or pagetoid spread of singet ring cells adjacent to DGC

  • Diagnosis of DGC and a family history of two first- or second- degree relatives with DGC or LBC (lobular breast cancer)

  • A diagnosis of DGC and a personal or family history of cleft lip / palate

Additional breast / ovarian cancer genes

• ATM gene

  • Bi-allelic mutations in ATM genes is Ataxia telangiectasia

• BARD1

• BRIP1

• CHEK2

• MSH2 / MLH1 / MSH6 / PMS2 / EPCAM

• NF1

• PALB2

• RAD51C

• RAD51D

• STK11

Ataxia Telangiectasia

• ATM genes

  • Bi-allelic, autosomal recessive version of ATM gene mutation

• Clinical features

  • Very sensitive to ionizing radiation

  • Overall cancer risk of 38%

  • Progressive gait / truncal ataxia (wheelchair by 10)

  • Progressively slurred speech

  • Immunodeficiency

  • Endocrine abnormalities (diabetes / premature ovarian failure)

Bloom Syndrome

• BLM gene

  • Autosomal recessive

  • Higher in Ashkenazi Jewish

• Clinical Features

  • Skin, breast, hematological, tongue, laryngeal, GI, cervical cancers

  • Diarrhea and vomiting in infants

  • Cafe-au-lait spots

  • Susceptibility to infection

  • High-pitched voice

  • Azoospermia

  • Learning disability with normal intellect

FA-BRCA Pathway

PTEN-Related Proteus-Like Syndrome

• Undefined but refers to individuals with significant clinical features of PS (proteus syndrome?) who do not meet the diagnostic criteria for PS