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?
- 5%-10%
- what percentage of patients who have personal/family history of cancer are referred for genetic counseling?
- 5%-7%
- 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
inheritable
cause cancer family syndromes - somatic mutations
-
occur in nongermline tissues
nonheritable - 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
cancer
-precursor lesions,
bilateral cancer
Record ethnicity & Race
Verify family history -
pedigree signs
1)male
2)female
3) death
4)affected
5)proband -
1)square
2)circle
3)slashed
4)shaded
5)arrow - 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
- T
- Genes associate w/ cancer predisposition
-
Tumor suppressor genes
- cells breaks for tumor
growth
- 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
Oncogenes
- accelerates cell
division
- cancer arises when
stuck on mode - Genes implicated in hereditary breast cancer
-
BRCA1-br, ovar, prost, etc
BRCA2- br, ovar, pancreas,etc
Li-Fraumeni
AT
Cowden - BRCA1
-
-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
- 2-35%
- strongest indicator of BRCA1 carrier
- breast & ovarian in same person
- BRCA2
-
-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?
- 5%
- 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
-
colorectal
endometrial
ovary
stomach other (GU,GI, brain) - HNPCC increases risk of second cancer T/F
- T
- 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
-A.D.
-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)
-AD