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What are the two genes associated with inherited cases of breast cancer called?
BRCA1 and BRCA2
how do BRCA1 and BRCA2 function normally? abnormally?
-when functioning normally, these 2 genes act as tumor suppressor genes. This means that they help repair DNA damage and prevent cancer cell formation
-if these genes become mutated, this can lead to the development of breast or ovarian cancer
what % of all breast cancers are associated with BRCA1 and BRCA2 mutations?
what is the avg US woman’s chance of developing breast cancer? how does this stat change if the woman has a BRCA gene mutation?
It is estimated that an average woman in the US has a *12%* chance of developing breast cancer in her lifetime. This risk increases to up to *85%* if the woman has a mutated BRCA1 or BRCA2 gene
occurs by chance… people with this type typically don’t have relatives with this type
caused by a combination of genetic and environmental factors
an altered gene is passed down in the family from parent to child
what are some signs of a BRCA2 mutation?
-both males and females are affected, and there’s no sign of ovarian cancer
How many nucleotides does BRCA2 contain? How many mutations? What do these mutations do to the DNA? What will happen to the protein produced by this gene?
-the BRCA2 gene contains more than 80,000 nucleotides and is larger than the average gene
-Researchers have identified more than 600 mutations in the BRCA2 gene, many of which are associated with an increased risk of breast cancer.
-Many BRCA2 mutations insert or delete a small number of nucleotides in the gene.
-Because the BRCA2 gene is a tumor suppressor gene, the mutation will result in a protein that is unable to help repair damaged DNA or fix mutations
technique where the gene mutation is analyzed using a genetic marker instead of directly analyzing the gene itself
-short sequence of DNA associated with a particular gene or trait with a known location on a chromosome
the genetic markers used in marker analysis are…
short DNA sequences called short tandem repeats
names for short tandem repeats
An STR is…
a region of DNA composed of a short sequence of nucleotides repeated many times.
do different ppl have different # of STRs?? what does this mean???
Yes: the number of repeated sequences in a given STR varies from person to person.
The alternate forms of a given STR correspond with different alleles
how can we use STRs to distinguish ppl?
Most STRs occur in gene *introns* (non-coding regions of DNA) so the variation in the number of repeats does not usually affect gene function, but we can use STRs to differentiate between different alleles.
relationship between the gene of interest and the genetic marker
because pieces of DNA that are near each other on a chromosome tend to be inherited together, an STR that is located on chromosome 13 next to the known BRCA2 mutation can be used as the genetic marker for this case
how will this genetic marker testing work? (starting with collecting samples)
1. DNA is extracted from each family member
2. The region of DNA containing the STR which is going to be used as the genetic marker for this mutation is amplified using PCR
3. The amplified DNA will then be run on a gel using gel electrophoresis
—because different alleles have a different number of repeats present in the STR, gel electrophoresis will separate different alleles based on the # of repeats present
4. the more repeats present in the STR, the longer the DNA fragment will be
what is loaded in the first well of the gel?
DNA size markers (a set of DNA fragments of known molecular sizes). They can be used as a standard to determine the sizes of unknown fragments
the known molecular sizes (weights in base pairs) for each marker are written to the left of each band.
to construct a standard curve, you need to…
plot the relative mobility value (Rf) for each standard marker versus their molecular size in base pairs on a semi-logarithmic graph
Rf is BASICALLY
how fast the DNA moves
women who have an abnormal BRCA1 or BRCA2 gene have…
a 50-80% risk of breast cancer by the age of 70. Lifetime risk of ovarian cancer is also increased
nutrition (preventative measures of cancer)
overweight women are thought to be at higher risk for breast cancer because the extra fat cells make estrogen, which can cause extra breast cell growth. Also, eating without pesticides may protect against unhealthy cell changes associated with pesticide use in animal studies
physical activity (preventative measures of cancer)
exercise consumes and contains blood sugar and limits blood levels of insulin growth factor, a hormone that can affect how breast cells grow and behave
hormonal or anti-estrogen therapy (preventative measures of cancer)
estrogen makes hormone-receptor-positive breast cancers grow. So reducing the amount of estrogen or blocking its action can reduce the risk of early-stage hormone-receptor-positive breast cancers coming back after surgery
surgery that removes one or both breast to reduce the risk of developing breast cancer by 90-95% *in those that have a BRCA mutation)
What is the harm associated with breast cancer screening?
Risk for false-positive findings
How does screening possibly cause harm?
Screening leads to identification of a breast cancer that would not have caused clinical consequences in a women’s lifetime had it not been detected
All pts with dx of breast cancer, regardless of stage, require what?
Some sort of local therapy; surgery with or without radiation therapy & often systemic therapy
Is it possible to distinguish biologically insignificant cancers from those that will proceed to grow, metastasize & lead to pt’s death?
No, not possible
What is the most common cause for hereditary breast & ovarian cancers?
Presence of germline mutations in tumor suppressor genes
& breast cancer type 1 & 2 susceptibility genes (BRCA 1 & 2)
What is the criteria for genetic risk evaluation for breast cancer and/or ovarian cancer?
Known mutation in family of a gene
Breast ca dx <50 years
Triple negative breast cancer dx <60 years
2 breast ca (in a single pt)
Breast ca dx at any age in addition to dx in relative
From Ashkenazi Jewish descent
What is considered first degree relative?
What is considered second degree relative?
What is considered third degree relative?
These features indicated increased likelihood of having what type of mutation:
Multiple cases of early onset breast cancer
Ovarian cancer (with family hx of breast or ovarian cancer)
Breast & ovarian cancer in same woman
Bilateral breast cancer
Ashkenazi Jewish heritage
Male breast cancer
What is the percentage of risk for breast cancer for BRCA1- associated cancers?
What is the percentage of risk for secondary primary breast cancer for BRCA1- associated cancers?
What is the percentage of risk for ovarian cancer for BRCA1- associated cancers?
What can BRCA 1 also increase risk of?
Prostate & colon cancers
What factors put a person at a higher risk for breast cancer?
Hx of chest radiation
Hx of breast ca
Extremely dense breasts compared with fatty breasts
Hx biopsy with atypical hyperplasia
Two 1st degree relatives with breast ca vs none
One 1st degree relative with breast cancer vs none
Menopause >55 yrs compared with <45 yrs Nulliparity or 1st term pregnancy >30
Hx benign breast biopsy vs no breast biopsy
Menarche at what age puts person at higher risk for breast cancer?
Menarche before age 12 yrs
True or false: current use of combination menopausal hormone therapy increase risk for breast cancer
True or false: Moderate alcohol use compared with abstention increases risk for breast cancer
Which resource omits breast density as risk factor?
NCI Breast Cancer Risk Assessment Tool
True or false: NCI Breast Cancer Risk Assessment Tool is more accurate for women with markedly positive family hx & women over 70 years
False, less accurate
What does Breast Cancer Surveillance Consortium focus importance on?
Breast density & age
For whom is the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, & Family History Screen 7 useful for?
Women with family hx of breast cancer
True or false: Many women who develop breast cancer do not fall into a clear high-risk group
True or false: No low-risk groups, other than young age, have been identified in which screening can clearly be omitted
By what percentage does screening reduce breast cancer mortality?
Screening causes reduction in breast cancer mortality smaller magnitude & less statistically significant for which age group of women?
Reduction is highly significant with screening in which age group of women?
Reduction has not been shown to be significant in which age group of women with screening?
True or false: screening has shown to reduce all-cause mortality
What are the harmful effects of false positive results?
Unnecessary follow-up tests & biopsies
Anxiety & psychological distress
What are the harmful effects of overdiagnosis?
Cancer that would never have progressed to clinical importance in absence of screening
Harms of tx without any benefit
Once cancer is dx, no way to determine whether it is case of overdiagnosis
What is another harm of screening?
Radiation exposure- small risk
Initiating screening at age 40 averts how many breast cancer deaths?
1 per 1000 deaths in women among ages 45-49
What percentage of breast cancer deaths were attributed to dx at age >74?
How often should screening occur until remaining life expectancy is about 10 years?
Biennial- estimated to reduce breast cancer deaths & harms for women in their 70s
Benefit of screening is low among women greater than what age?
What are the risk factors for women aged 40-49; more than 2 fold increased risk?
1st degree relative with breast ca
Age of 1st degree relative with breast ca <40-50
Prior benign breast biopsy result
2nd degree relative with breast cancer
Breast density BI-RADS category 3
What are the risk factors for women aged 40-49; 1.5- 2.0 fold increased risk?
Prior benign breast biopsy result
Second-degree relative with breast cancer
Breast density BI-RADS category 3
What are the risk factors for women aged 40-49; 1.0-1.5 fold increased risk?
Current oral contraceptive use
Age at first birth >30 years
Who is annual screening recommended for?
Women with higher risk of breast cancer
Women who value a greater mortality benefit even at expense of higher likelihood of false positive result or overdiagnosis
Does sensitivity & specificity of digital mammography increase or decrease with age?
Does sensitivity & specificity of digital mammography increase or decrease with increasing breast density?
Does 3-D mammography (tomosynthesis & digital mammography) improve or reduce sensitivity & specificity?
Is contrast-enhanced MRI more or less sensitive/specific than mammography?
More sensitive but less specific
What screening method is best for average risk women?
What screening method is best for increased breast cancer risk?
What screening method is expensive & has lack of evidence for effectiveness in average-risk women bc of excessive false positives?
What screening method has no evidence that it improves results over mammography screening for average-risk women?
Does instructing average risk women to do breast self-exam improve mortality?
No, causes excess benign biopsies
What can be added to mammography for high risk patients?
What should be considered when making a decision about screening?
Personal level of risk
What is appropriate for women with extremely dense breasts & those with 1-2 first degree family members with breast cancer?
Annual screening & digital breast tomosynthesis
Who should the MRIs be reserved for?
Women who are very high risk
What is the role of genetic counseling?
Reduces worry about breast cancer & increases the accuracy of risk perception
Who should be offered genetic counseling & testing?
Women with ≥1 family members with BRCA1 / BRCA2 mutation
What are the options for prevention in eligible women?
What type of healthy behaviors can reduce breast cancer risk?
Physical activity reduces breast cancer risk about 12%
Diets high in fruits and vegetables modestly reduce risk
Alcohol use increases risk in a dose-response effect
Vitamins E and D do not reduce breast cancer risk
For women with hereditary breast cancer mutations, what is an effective alternative to chemoprophylaxis?
Prophylactic bilateral mastectomy
What do selective estrogen receptor modulators (SERMS) ex. Tamoxifen, Raloxifene- do?
Stimulate some estrogen receptors while blocking others
Reduce risk for ER invasive breast cancer
What do aromatase inhibitors (AIs) ex. Anastrazole, exemestane- do?
Inhibit the enzyme aromatase, which converts androgens to estrogens
What are the harms of SERMs?
Tamoxifen: endometrial cancer and VTE (RR 2.0) for women ≥50 yrs
Raloxifene: VTE risk but not endometrial cancer risk
What are the harms of AIs?
Anastrozole: musculoskeletal side effects, hypertension, vaginal dryness, vasomotor symptoms
Exemestane: joint pain, diarrhea, vasomotor symptoms
Tamoxifen or raloxifene: women more likely to remain sexually active & to have less difficulty with sexual interest and enjoyment
more vasomotor symptoms, bladder problems, etc.
Tamoxifen or raloxifene: reduced risk for uterine cancer & slightly lower risk for VTE
more musculoskeletal problems, dyspareunia, & weight gain
What is the mainstay of screening for breast cancer?
What does mammography do?
Measure changes in the movement of protons in fat & water with the application of changing magnetic fields
What contrast agent needs to be administered for mammography?
What are the two most important mammography indicators of breast cancers?
What are microcalcifications?
Tiny flecks of calcium – like grains of salt – in the soft tissue of the breast that can sometimes indicate an early cancer
What type of appearance do malignant masses have?
What type of tissue may hide tumors?
The breasts of which women contain more glands & ligaments resulting in dense breast tissue?
With age, breast tissue becomes more what?
Fatty & has fewer glands
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