Lecture 2: Hereditary Breast, Ovarian, Colorectal Cancer

Question 1

cancer (4)

Answer 1

1. disease characterized by uncontrolled growth and spread of abnormal cells
2. results from serious of molecular events that fundamentally alter the normal properties of cells
3. different degrees of tumor, different stages
4. both GENES and ENVIRONMENT important

Question 2

Cancer as a genetic disease (4)

Answer 2

1. second only to cardiovascular disease that is most common death in Western, industrialized nations
2. most cancer cases are sporadic
3. less than 10% tumors results form familial disposition
4. ALL cases, sporadic or familial have a GENETIC CAUSE

Question 3

Genetic of Cancer (4)

Pathophysiology?

Answer 3

1. most types develop through PROGRESSIVE ACCUMULATION of various mutations within a cell
2. Mutations typically acquired somatically (after conception)
3. some mutations are transmitted through germ line and are present at birth in every body cell
4. Pathophysiology: balance between cell proliferation and survival and cell cycle arrest and apotheosis is disrupted in cancer*

Question 4

Two genes responsible for cancer development

Answer 4

1. protoncogenes

2. tumor suppressor genes

Question 5

Proto-oncogenes (3)*

Answer 5

1. group of genes that cause normal cells to become cancerous when they are mutated
2. mutations are typically dominant* in nature
3. Proto-oncogenes encode proteins that function to stimulate cell division, inhibit differentiation, and halt cell death

DOMINANT AT CELLULAR LEVEL

Question 6

oncogene

Answer 6

mutated version of proto-oncogene

Question 7

Tumor Supressor Gene (3)*

Answer 7

1. relevant for the regulation of growth, repair, and cell survival
2. malignant transformation supported through recessive loss of function mutations on both* copies of gene
3. typically include DNA repair genes responsible for detecting and repaiting genetic damage within cell

Question 8

DNA Repair Genes

Answer 8

within tumor suppressor genes

responsible for detecting and repairing genetic damage in cell

Question 9

Proto-oncogene -> Oncogene (4)

Answer 9

1. oncogenes develop mutations that result in a gain* of function
2. mostly missense mutations that cause permanent activation or altered function of the gene product
3. porto-oncogenes can also be duplicated or multiplied (amplified) = increased gene copy numbers and thus more gene products in the cell
4. transnolcations can turn a photo-oncogene into an oncogene
   - generated fusion gene with novel function and placing it under control of a new, constitutively active promote which might trigger abnormal expression with regard to organ system of developmental stage

Question 10

translocations

Answer 10

can turn proto-oncogene into an oncogene

Question 11

Tumor Supressor Gene (5)

Answer 11

1. most familial cancer predisposition results form mutations in tumor suppressor genes in which loss of function favors development of a tumor
2. products inhibit cellular growth, proliferation or cell cycle progression (gatekeeper genes)
3. ensure genetic stability, through DNA repair (caretaker genes)
4. inactivating mutations in both* alleles is needed
5. RECESSSIVE AT CELLULAR LEVEL

Question 12

BRCA Genes 1 & 2 (2)

Answer 12

1. tumor supressor genes
   - code proteins involved in damage repair
   - involved in cell cycle control and regulation of other proteins on DNA damage response
2. familial breast cancer caused my mutations in these genes are autosomal dominant

Question 13

BRCA 1 location

Answer 13

chromosome 17q21

-can cause prostate cancer rx in men (rarely breast)

Question 14

BRCA 2 location

Answer 14

chromosome 13q21

• can cause breast cancer rx in men, 7% risk in 70 years
• can cause pancreas, larnyx, esophagus, colon, stomach, bilary tract, and menalonomas (in male and female)

Question 15

Founder effect

Answer 15

1. reduction of genetic variation that happens when a small group of individuals starts a new population

a. mutations specific to family
b. general populations
- 1 in 800 with BRCA 1 or BRCA 2 mutation
c. ashekanci individuals
- 1 in 40 have BRCA 1 or BRCA 2 mutation

Question 16

Targeted mutation analysis

Answer 16

may be offered to women of specific ethnic background

-includes mutations known to be at greater frequencies because of founder effects

Question 17

Comprehensive analysis

Answer 17

includes full sequence analysis of BRCA 1 and BRCA 2 and testing for specific large genomic rearrangements of BRCA 1

Question 18

expanded panel testing

Answer 18

BRCA 1/2 and multiple, other high risk gene mutation

Question 19

Genetic testing available to detect mutations in BRCA 1 and BRCA 2 (3)

Answer 19

1. targeted mutation anaylsis
2. comprehensive analysis
3. expanded panel testing

Question 20

Penetrance (2)

Answer 20

1. Probability of developing disease in a carrier of a deleterious mutation
   - usually defined in terms of given age
2. Risk of cancer in individuals with BRCA 1 or BRCA 2 mutation may be modified by a second gene or by an environmental factor

Question 21

Estimates of Penetrance by age 70 years for BRCA 1 and 2 (2)

Answer 21

1. 64.6% BRCA 1
   61% BRCA 2
   -breast cancer
2. 48.3% BRCA 1
   • 20% BRCA 2
     - ovarian cancer

Question 22

Somatic mutation profiles (4)

Answer 22

1. detection of mutations within a tumor (not necessarily gremline)
2. treatments based on tumor genome
3. correlation of clinical outcome and prognosis
4. researchers can link mutations with specific molecular mechanisms- potentially revealing therapeutic targets

Question 23

Li-Fraumeni Syndrome

Gene on which chromosome?

caused by mutations on which gene?

5 complications

Answer 23

rare associated syndrome

1. genome mutation on chromosome 17
2. caused by mutations on E-cadherin gene CD1
3. premenopausal breast cancer
   - avg age onset 36 years
4. childhood sarcoma
5. brain tumors
6. leukemia
7. adrenocortical carcinoma

Question 24

Cowden syndrome (7)

5 complications
genes involved, type gene

Answer 24

1. rare syndrome assoc. with breast cancer
2. bening hamartomas
3. excess of breast cancer
   - lifetime rx 25-50%
   - onset early
   - often bilateral
4. GI malignancies
5. endometrial cancer
6. benign or malignant thyroid disease
7. 4 genes linked to cowden sndrome
   - 80% with mutations in PTEN
   - tumor supressor, autosomal dominant inheritance

Question 25

Peutz-Jeghers syndrome (4)

what gene mutated, type of gene?

complications

Answer 25

1. rare syndrome assoc. with breast and ovarian cancer
2. mutations in STK 11 (tumor supressor)
3. autosomal dominant
4. increased rx of developing cancer
   - GI , polyps, malignancies
   - cervix
   - ovary
   - breast

Question 26

Management options breast cancer (2)

Answer 26

1. breast immaging
   - mammography
   
   • > annually beginning 25-35 years in female carriers of BRCA1 or BRCA2 mutation
2. MRI
   - annual screening in addition to mammography for women at hereditary risk for breast cancer
   - more sensitive then either mammography or ultrasound
3. masectomy

Question 27

Elective Risk-reducing mastectomy factors

Answer 27

1. depends on
   - age
   - culture
   - geography
   - healthcare system
   - insurance coverage
   - provider attitudes
   - social factors

Question 28

ovarian cancer screening (3)

Answer 28

1. annual/semiannual screening
2. transvaginal ultrasound and serum CA-125 levels for women with higher in hearted rx ovarian cancer
3. prophylactic bilateral sapling-oophorectomy is recommended between ages 35-40 years or upon completion of childbearing

Question 29

Colorectal cancer (4)

Answer 29

1. Cells lining colon or rectum become abnormal and grow out of control
2. majority are sporadic
3. familial or hereditary patterns need to be recognized early using screening and management guidelines in both parents and relatives
4. many patients with colorectal cancer do not experience any symptoms until the disease is advanced

Question 30

signs, sx colorectal cancer (10)

Answer 30

1. blood in stool
2. weight loss with no known reason
3. diarrhea not a result of diet or illness
4. long period of constipation
5. crampy abdominal pain
6. change in bowel habits
7. unexplained anemia
8. persistent decrease in size or caliber of stool
9. frequent feeling of abdominal destention
10. vomiting and continual lack of energy

Question 31

Colon cancer screening

Answer 31

adults 45-75 should be screened, after 75 decision is made on individual basis

Question 32

Familial Colorectal cancer (4)

Answer 32

1. 15%-30% colorectal cancers
2. patterns with a family that exist without identification of a specific mutation are considered familial
3. result of single gene mutation, multiple gene mutations, or combined effects of gene mutations and environmental risk factor
4. family hx of one or more members with frank colorectal cancer or premalignant polyp should be considered significant

Question 33

Hereditary colorectal cancer 20 types

Answer 33

1. familial ademonatous polyposis coli (FAP)

2. Hereditary non-polyposis colon cancer (HNPCC)

Question 34

Familial adenomatous poluposis coli overview (3)

Answer 34

1. Gene termed APC
2. adenomas start as polyps, many*
3. can progress to malignancy

Question 35

Hereditary non-polyposis colon cancer overview (3)

Answer 35

1. Disease termed HNPCC or lynch syndrome
2. less polyps
3. other tumors also common

Question 36

familiar adenomatous polyposis (FAP) (3)

Answer 36

1. autosomal dominant-50% chance of passing condition to children
2. individuals who inherit mutated APC gene have a very high likelihood of developing colonic adenomas
   - onset variable
   - APC=tumor supressor gene
3. loss of second copy of gene causes polyp formation
   - several hundred may form
   - not sufficient for cancer progression

Question 37

Genetics FAP (5)

Answer 37

1. APC tumor supressor gene mutations
   - premature stop codons shorten APC gene product
   - role in regulation of cell adhesion and apoptosis
2. location of mutation on chromosome 5 affects the number of polyps formed and the type extracolonic features seen
3. FAP caused by MYH mutation is inherited in an autosomal recessive fashion
4. patients with classic FAP:
   - 90% have mutation in APC gene
   - 8% with mutation in MYH gene
5. patients with attenuated FAP
   - 15% with mutation in APC
   - 25% with mutation in MYH

Question 38

Genetic counseling, testing, screening for FAP (8)

Answer 38

1. offered to patient w diagnosis FAP
2. offered to at risk relatives of patients with FAP
3. individuals with 20 or more adenomas
4. MYH testing should be considered in pattens with negative APC results, and suspected attenuated FAP
5. children of patients with FAP should undergo genetic screening at age 10
6. annual colonoscopy (if genetic testing cannot be done) beginning at age 12
7. upon dx, completely protocolectomy or colectomy is recommended before age 20
8. it attenuated FAP suspected, it is important that family members be screened with colonoscopy rather than flexible sigmoidoscopy

Question 39

Hereditary Nonpolyposis colorectal cancer (6)

Answer 39

1. AKA Lynch syndrome
2. autosomal dominant
3. 3-5% all colorectal cancers
4. only a few ademonas, usually on R side colon
5. occurs at a younger age than sporadic colorectal cancer
6. other cancers may arise in these families including
   - uterine
   - ovarian
   - stomach
   - urinary tract
   - small bowel
   - bile ducts

Question 40

Amsterdam II

Answer 40

Criteria to dx HNPCC

1. 3 or more relatives with a lynch assoc. cancer (colorectal, endometrial, small intestine, ureter, renal pelvis)
2. 2 or more successive generations affected, one is a first-degree relative of the other two
3. 1 or more relatives is diagnosed before the age of 50
   and* familial adenomatous polyposis has been ruled out
4. tumors verified by pathologic examination

Question 41

Bethseda Criteria (5)

Answer 41

1. colorectal cancer in patient < age 50
2. Synchronous or metachornous colorectal cancer or other lynch-related tumors (any age)
3. colorectal cancer with micro satellite instability histology in patient < 50 years of age
4. colorectal cancer/lynch-related tumor in 1 or more first-degree relatives; 1 < age 50
5. colorectal cancer/lynch-related tumor diagnosis in 2 or more first-second degree relatives

Question 42

Genetics HNPCC (3)

Answer 42

1. defect in one of several genes
   - MLH1, MLH2, MSH6, PMS2
   - all involved in DNA mismatch repair
   - loss of function increased mutation rate 1,0000x
2. families should be evaluated first by genetic counselor and give informed consent before genetic testing is performed
   - genetic screening should be considered for patients meeting any of the revised Bethesda criteria
3. if genetic testing documents an HNPCC gene mutation, affected relatives should be screened with colonoscopy every 1-2 years
   - begining at age 25

Question 43

Internal Factors Cancer (4)

Answer 43

1. inherited mutations
2. hormones
3. immune conditions
4. mutations the occur during cellular processes

Question 44

External Factors (4)

Answer 44

1. tobacco
2. infectious organisms
3. chemicals
4. radiation

Question 45

Two hit hypothesis

Answer 45

Cancer development involved two successive mutations that affect the two alleles of a tumor suppressor gene

in familiar cancer disposition syndromes, a mutation on one allele is inherited and only one additional hit is required for cancer development

Question 46

Tumorigenesis involving BRCA 1 and BRCA 2

Answer 46

1. based on 2-hit hypothesis
2. requires inactivating os second, normal allele by mutation or large deletion
   a. appearance of cancer depends on where the second mutation occurs
   b. cancer can seem to “skip” a generation within a family

Question 47

Colorectal Polyps

Answer 47

benign adenomatous growths protruding from the mucous membrane of the colon and rectum
-if left untreated, may evolve into cancer