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Monica Alverez-Cancer Genetics


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in cancer genetics is family history in mom or dad more important?
fathers side of family is just as important as mothers
what percentage of cancer is hereditary?
what percentage of patients who have personal/family history of cancer are referred for genetic counseling?
What tools do clinitians need to ID patients who need genetic counceling?
1) ID high risk family histories
2) recognizing morphological/ histological features
3)access to resources
genetic vs. inherited?
cancer is always genetic but rarely inherited
germline mutations
present in egg or sperm
cause cancer family syndromes
somatic mutations
occur in nongermline tissues
Taking family history
3 generation pedigree
all individuals on both sides of family and record
-age at cancer diagnosis
& age of dealth
-primary vs metastatic
-precursor lesions,
bilateral cancer
Record ethnicity & Race
Verify family history
pedigree signs
3) death
Hereditary Cancer
-cancer in 2 or more close reletives on same side of family
-early age at diagnosis
-multiple primary tumors
-bilateral or multiple rare cancers
-constellation of tumors consistent w/ specific caner syndrome (e.g., breast & ovary, colon & endometrium
-evidence of autosomal dominant transmission
autosomal dominant inheritance
-each child has 50% chance of inheriting the mutation
-no "skipped generations"
-equally transmitted by men & women
elements of cancer genetics evaluation
-risk assessment
-education & counseling
-psychosocial assessment
-informed conssent
-genetic testing
-result intermpretation
-risk management plan
T or F: Begnin by testing affected reletive of proband
Genes associate w/ cancer predisposition
Tumor suppressor genes
- cells breaks for tumor
- cancer arises when both
braks fail
DNA damage-response genes
- the repair mechanisms
for DNA
- Cancer arises when both
genes fail, speeding the
accumulation of
mutations in other
critical genes
- accelerates cell
- cancer arises when
stuck on mode
Genes implicated in hereditary breast cancer
BRCA1-br, ovar, prost, etc
BRCA2- br, ovar, pancreas,etc
-1/500 women carriers
-mutations scattered through out gene
-breast tumors EstrogenReceptor neg(unusual)
-male carriers can pass gene on
-specific alterations in Ashkenazi Jewish individuals
percentage of women who will get breast cancer
8% (1/12)
Inherited risk of cancer if have BRCA1
strongest indicator of BRCA1 carrier
breast & ovarian in same person
-gene 2ce as big as BRCA1
-breast tumors ER+
-age of br cancer tends to be older
-wider spectrum of cancer types
-specific alterations in Ashkenazi Jewish individuals
-more likely to have affected male in pop.
Ashkenazi Jewish Individuals
-1/40 have mutation in BRCA1/2 regardless of family history
-founder effect (3 mutations accont for majority of carriers)
option for BRCA mutation +
-lifestyle changes
-increased surveillance
-prophilactic surgery
-chemo prevention
BRCA1/2 Key points
-only 5%-10% of b/o cancer is inherited
-BRCA 1/2 are most common genes involved in inherited br/ov cancer susceptibility
- not all HBOC genes
known, family may still
be high risk even if
no mutation is found
- Mutations in BRCA1/2
- can be passed down by mom or dad
- more freequent in Ashkenazi Jewish families
- inherited in autosomal dominant fashion
-genetic testing can ID mutations in BRCA 1/2 & influence risk management
- risk reducing surgery should be offered to carriers
colorectal cancer
-2rd most common cancer in US
-most develop from polyps
-screening can prevent
-effets men & women equally
-diet & excercise big factor
-no BBQ meat
-60% sporadic/30% familial (clusters in family)
Percent of cancers inherited?
risk increases for colorectal cancer?
number of effected relatives & earlier age of onset of cancer
HNPCC clinical charististics
-5% of colorectal cancer
-earlier age of onset(<45y/o)
-defects in 1 of 5 mismatch
repair genes
-tumors tend to be R sided
-improved survival vs other cancers
HNPCC cancer risks
stomach other (GU,GI, brain)
HNPCC increases risk of second cancer T/F
HNPCC Fast Facts
-known as lynch syndrome
-2-7% annual world wide insidence of colorectal cancer
-autosomal dominant inheritance
-40-60% pts test + for mutation
-extra colonic cancer risks gender specific
-CRC risk higher in males than females
genes responsible for HNPCC
mismatch repair (MMR) genes
Microsatellite Instibility is found in what cancer
HNPCC (95%)
Surveilance for HNPCC carriers
1) colorectal cancer
2) endometrial cancer
1) Colonoscopy -begin 20-25 reapeat every 1-2 yrs, anual at 20
2) Transvaginal ultrasound - begin 25-30 anually
recommendation guidelines for HNPCC screening
1) Amsterdam
2) Bethesda
HNPCC: key points
most common form of heridetary CRC
-uterine/endometrial cancer 2nd most common after CRC in HNPCC families
- polyp number not increased above gen. populations
-family/personal history and MSI/IHC can help ID affected individauls
-genetic testing in HNPCC can ID mutation carriers
-colonoscopy survelance can improve survival in at risk individauls
-bnefits of surveilance for most extracolonic cnacers are still unknown
-noncarriers can be spared anxiety and the need for increased surveilance
Familial Adenomatous Polyposis(FAP)
-early onset CRC - 35 yo
-significant # polyps
-tumor supressor gene
-~100% CRC penetrance by age 40
-30% arise from new mutation
-CHIRPE may be present (retina freckels)
Garners Syndrome
-Varient of FAP
-dental abnormalities
-benighn sist
-ST tumors
FAP: Key pts
-AD, early onsit
-30% no family hx
-many polips
-risk 100% w/out treatment
-genetic testing of children has medical benefit
Factors that suggest inherited susceptibility
-early onset
-more than one primary site
-bilatral disease
-close reletives w/ same related cancer
-rare presentations (e.g., male breast cancer)

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