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 65-85 %

HNPCC 5 %

Familial 10-30 %

FAP 1 %

Vogelgram:

APC failure Mutation K-ras Mutation DCC Mutation/loss p53

·  Mismatch repair genes [“caretaker genes”] : *MSH-2, *MLH-1, PMS-1, PMS-2, MSH-6, MSH-3

·  APC = “gatekeeper”

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

·  pelvic examn annually ( age 25-35 )

·  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

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