Download ovarian cancer - Pass the FracP

DR McCrystal – CANCER and GENETICS
SOME DEFINITIONS
 Nonsense mutation : forms stop codon  truncate
 Missense mutation : point mutations that aren’t nonsense mutation (ie mutation that
doesn’t form stop codon)
COLORECTAL CARCINOMA
Sporadic
HNPCC
Familial
FAP
65-85 %
5%
10-30 %
1%
Vogelgram:
APC failure
Mutation K-ras
Accelerated
growth


Mutation DCC
Early
adenoma
Mutation/loss p53
Late
adenoma
Mismatch repair genes [“caretaker genes”] : *MSH-2, *MLH-1, PMS-1, PMS-2, MSH-6,
MSH-3
APC = “gatekeeper”
Carcinoma
APC gene
Chromosome 5q (long arm)
Mutations assoc with 2 cancer syndromes:
1.
Familial Adenomatous Polyposis (FAP)
 Classically >100 polyps colorectum (adenomata) appear by teens, early 20s
 1:7000 – 1:8000 autosomal dominant
 penetrance for adenomas >90%
 100% pts with phenotype develop malignancy
 30% pts = de novo mutation
 10-12% lifetime risk duodenal ulcer (around sphincter of Oddi)
 Extracolonic manifestations
 Congenital hypertrophy of retinal pigment epitheliums (CHRPE)
 Desmoids
- cutaneous, soft tissues
- intra-abdominal (mesenteric)
VARIANTS:
 Gardner’s synd : polyposis/osteomas/epunumerary teeth/desmoids
 Attenuated FAP
 Mutations at extreme ends of genes
 < 150 polyps
 later onset ~50 yrs
 upper GI lesions can occur
 Turcot’s synd
 Hereditary desmoid synd
2.
I 1307 K Missense Mutation (controversial)
 Change in single base creates poly-A tract  “hot spot” for further mutation
 Ashkenazi Jews  phenotype similar to sporadic colorectal carcinoma (no excess
polyps)
Note with APC genotype/phenotype correlations
Mutations btw codons 1250 – 1464 = profuse polyps
463 - 1387 = CHRPE
1403 – 1578 = Gardner phenotype
MUTATION DETECTIONS
 Protein Truncation (false negative = 10%) – most reliable gene test for FAP
 Allele Specific Assays  for I 1307K mutation
SURVEILLANCE/PROTECTION/PREVENTION for FAP
 Gene test age 10-12 yrs
 + mutation  annual colonoscopy
 adenomas found or late teens/early 20s
consider prophylactic colectomy + (?chemoprevention)





HNPCC (Lynch syndrome)
early but variable age onset carcinoma
predominant site proximal colon
associated with
carcinoma :
Endometrium
Ovary
Renal (collecting system)
Biliary tree
Small bowel/stomach
43%
9%
10%
18%
19%
Sebaceous cyts
Amsterdam criteria:
 3 or more relatives with colorectal cancer
 1 case first degree relative of the other
 spans 2 or more generations
 [ FAP excluded ]
due to mismatch repair failure
 germline mutation in MMR
“second hit” in affected organ
Phenotype = “replication error repair” [RER] phenotype
= microsatellite instability



L MSH-2 = 30% cases
H MLF-1 = 30%
Others rare
Majority of mutations being inactivating
insertions, deletions, nonsense mutations;
some missense mutations
Detected by DGGE  sequencing
(protein truncation has high false negative rate)
NB :
 Paradox : RER positive has better prognosis than sporadic mutation
 Microsatellite instability in 15% sporadic tumours (ie not confined to
HNPCC )
 Microsatellite instability is most useful as indicator of MMR (mismatch
repair) of germline nature in pts < 35yrs old
HNPCC “Carriers”
 Consider subtotal colectomy in individuals with colon cancer (risk metachronous
malignancy)
 Nonaffected individuals (family risk or gene positive)
 colonoscopy 1-3 yrs
Because of endometrial Ca
 pelvic examn annually ( age 25-35 )
risk
 transvaginal u/s annually (age 25-35 )
 consider hysterectomy/BSO - if positive family history of
endometrial Ca


BREAST CARCINOMA
5-10% breast Ca demonstrate autosomal dominant-type transmissions
known gene account for 50-60%
BRCA-1
 chromosome 17
 large gene 5592 base pairs, 22 coding exons  1863 amino acid protein
suppressor gene function (RAD 51) ? exact mechanism
 “carriers” have 40-80% chance of developing breast cancer by age 80yrs
 approximately 500 mutations reported (spread across gene)
 note ovarian cancer 30-50% lifetime risk
 prostate cancer risk < 4 X population
 colon cancer risk initially thought to be ~ 6X population risk (but now estimated lower risk
and no longer requirement for sigmoidoscopy/colonoscopy screening)




breast Ca tend to be high grade, ER –
? prognosis different from sporadic
risk of 2nd primary breast Ca 5%/yr
Issues :
 ? bilateral mastectomy
 no evidence that ovarian cancer works
 for mutation carriers ,
 surveillance (?effectiveness)
 bilateral mastectomy/oophorectomy considered
BRCA-2
 large chromosome 13q
 10254 base pairs, 27 exons  3418 amino acid protein
 limited homology to BRCA-1
 similar lifetime breast cancer risk
 less ovarian cancer risk (10-20%)
 ?  risk prostate/pancreatic Ca
 Increased risk male breast cancer
BRCA-1 and BRCA-2
 Negative test doesn’t mean anything

Incidence of gene low in families with breast cancer in females alone (surprising)

Chances of detectable mutation discovery rise with :
 Bilateral breast Ca
 Ovarian cancer
 Male breast cancer
 Jewish Ancestry
Founder mutations :
185 del AG BRCA-1
5382 ins C
BRCA-1
6174 del T
BRCA-2
2% Ashkenasi population
OVARIAN CANCER

5% hereditary
BRCA-1
BRCA-2
HNPCC
Others
70%
20%
~ 2%
~ 8%
GASTRIC CANCER
McLeod family
E-cadherin mutation
MEDULLARY THYROID CANCER



RET oncogene
 MEN 2b = mutations exon 1b
 MEN 2a = mutations exons 10 + 11
 Medullary Thyroid Ca = mutations exons 10 + 11 (rarely 13 + 14)
Familial Hirschsprung’s Disease may also be associated with RET mutations
Familial Phaeochromocytoma – consider von Hippel Lindau
Li-Fraumeni Syndrome

p53 mutation
 sarcomas
 melanoma
 breast cancer
 brain tumours
 adrenocortical