Transcript Hereditary GI Cancer - Medical Oncology at University of Toronto

Hereditary GI Cancer-a Primer
for Medical Oncologists
Ophira Ginsburg, MD, MSc, FRCPC
Clinical Lead, Cancer Prevention & Screening
Director Familial Oncology
Central East Regional Cancer Program
March, 2009
Objectives
1.
HNPCC review
Diagnosis, genetic testing, cancer risks, risk
reduction strategies
2.
Other Hereditary GI syndromes:
FAP, AFAP/MAP, HDGC
3.
Criteria for referral to Familial Oncology Programs
Hereditary GI Cancer
Examples [gene]
•
HNPCC [MLH1, MSH2, MSH6, PMS2]
FAP [APC]
AFAP [APC, MUTYH1]
•
FHDG [CDH1]
•
•
Why do genetic testing?
To confirm there is a genetic
predisposition to cancer
 To predict which family members are
at increased risk of cancer
 To prevent cancer or detect it early

GENETICS SERVICE
Genetic Counselling Process
Standard
Timeframe
6-8 months
REFERRAL
•Triage
•Family hx forms
Seen <2wks
if urgent
Chart Prep
•Forms received
•Pedigree drawn
•Pathology
verification
Case conference/
Counselling +
Testing
(if indicated
/accepted)
Result session
•Follow-up appts
arranged
Courtesy of Lori Van Manen, 2008
What Happens During a Genetic
Counselling Session?
Risk Assessment
 Review of hereditary cancer
 Discussions regarding testing:

Pros
Obtain information about
personal risk
Provide incentives for
surveillance
Clarifies uncertainty
Patient empowerment
Assists ongoing research
Cons
Inconclusive results (often)
Feelings of guilt or anxiety
Family tensions
Ethical issues
Insurance issues
Decreased compliance with screening
History of Familial Oncology Programs

1995: counselling and genetic testing became
available through research in 1995.

2001: Ministry of Health established recommended
referral and testing criteria, and began funding
BRCA1/2 testing.

Since 2001: HNPCC counselling/testing funded
BUT. Local estimates of uptake/referrals given 5-10% CRC caused by
HNPCC, ~ 20-25% CRC incident cases *should* be referred. Est: 10%
capture so far
CRC
Lynch Syndrome in Family “G”

Dr. Aldred Scott Warthin, MD, PhD described
“Family G” in a 1913 publication based on records
ascertained from the University of Michigan hospitals
between 1895 and 1913.
Progenitor
site unknown
d. 60y
A
B
C
D
E
F
G
H
I
d. 47y
Site Unknown
d. 64y
Stomach
d. 84y
d. 26y
d. 63y
d. 55y
Colon, NOS
d. 42y
Rectum
d. 60y
Stomach
d. 55y
Uterus, NOS
Douglas et al. (2005) History of
Molecular Genetics of Lynch
Syndrome in Family G; JAMA;
Vol. 294 (17), 2195-2202
“Of the 48 descendants of the cancerous grandfather,
17 have died or been operated on for cancer. The
preponderance of carcinoma of the uterus (ten cases)
and of the stomach (seven cases) is very striking in
the family history” Dr. Warthin, 1913.
Why HNPCC is important

HNPCC/Lynch syndrome- 3 to 5 times more
common than FAP

Harder to diagnose: many non CRC tumours,
families with more “other tumours” than
colorectal

potential for 1 or 2 prevention of other
HNCC cancers: endometrial, urothelial, ovarian?
HNPCC -CRC Unique Features
Colorectal cancer:
• 70% right sided distribution
• Synchronous, metachronous primaries
• Pathology: mucinous, poorly differentiated, peritumoural lymphocytic infiltration
• Prognosis: ?
• Response to chemo?
HNPCC
Cancer
General Population
Risk
Risks
Mean Age of Onset
Colon
5.5%
80%
44 years
Endometrium
2.7%
20-60%
46 years
Stomach
< 1%
11-19%
56 years
Ovary
1.6%
9-12%
42.5 years
Hepatobiliary tract
< 1%
2-7%
Not reported
Urinary tract
< 1%
4-5%
~ 55 years
Small bowel
< 1%
1-4%
49 years
Brain/central nervous system
< 1%
1-3%
~ 50 years
Cancer risk (%) by age 70
Type of Cancer
MLH1
39
Female
CRC
MSH2
71
MSH6
Lower than
MLH1/MSH2
96
Male
Endometrium
42
61
Higher than
MLH1/MSH2
Ovary
3.4
10.4
specific risk unknown
Stomach
2.1
4.3
specific risk unknown
Small bowel
7.2
4.5
specific risk unknown
Urinary Tract
1.3
12
specific risk unknown
Other
specific risk unknown
Extracolonic- 11
Extracolonic -48
Family History in HNPCCmore than meets the eye
Lynch and de la Chapelle
HNPCC-criteria for testingbeyond Amsterdam*
Revised Amsterdam (ICG-HNPCC,
1999)
o
o
o
o
o
3 relatives with CRC or assoc
ca (uterine, small bowel,
ureter, renal pelvis)
1st degree of the other 2
2 successive generations
1 before age 50
Histological verification
50% by mutation analysis
Revised Bethesda (Umar et al,
2004)
o
o
o
o
o
CRC in pt under 50
Synch/metachronous, or
other associated ca
CRC with MSI under 60
CRC with one or more 1st
degree relative (under 50)
CRC with 2 or more 1st/ 2nd
degree relative (any age)
15% by mutation analysis
*R/O FAP
2 main classes of CRC:
different models of tumourigenesis

Chromosomal instability: 85% distal;
aneuploid; APC, p53 K-Ras mutations; more
aggressive; prototype FAP
“APC= the gatekeeper of CRC”

Microsatellite instability: 15%
proximal: diploid; MSI, MMR mutations;
less aggressive?, prototype HNPCC
“MMR genes = caretakers of CRC”
Genetic Testing in HNPCC

MSI- microsatellite instability (tumour)

IHC- immunohistochemistry (tumour)

Germ-line DNA for mutations in one of 3
genes (MLH1, MSH2, MSH6) PMS2
Amsterdam or research lab
Microsatellite instability




hallmark of tumours in HNPCC
Microsatellites: genomic regions with repetitive
short DNA sequences (often single nucleotides)
prone to mutation during DNA replication
Results in elongation or contraction = instability
Microsatellite Instability
•
When DNA polymerase inserts the wrong bases
in newly synthesized DNA, the “mismatch
repair” enzymes repair the mistake
•
Defects in mismatch repair genes (MLH1,
MSH2, MLH6) lead to the mutator phenotype:
high frequency microsatellite instability or
“MSI-H”
Gryfe et al, NEJM 2000
NEJM May 5,2005
Hampel et al
HNPCC: Risk Reduction Options
Colorectal


Unaffected: colonoscopy to cecum q 1-2 years
Affected w CRC: consider subtotal colectomy at
1st diagnosis d/t risk of 2nd primaries
http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf
Seminars in Oncology, Oct 2007
HNPCC: Risk Reduction
Gynecological Cancers
Screening for ovarian ca: CA125 + TVUS
jury still out- Lancet Oncology online Mar 09
Screening for endometrial ca:
annual TVUS + random endometrial bx (age 30+)
few studies: review Lindor et al, JAMA 2006
See also current NCCN guidelines
Surgical Options for Gyne Ca
Prophylactic BSO
Ovarian/FT risk reduction > 80-90%
nb/ primary peritoneal carcinomatosis ~5-7%)
Prophylactic TAH/BSO
-less studied but likely >90% RR for endometrial
ca in HNPCC mutation carriers
Recent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer
Inst. 2009;101(2):80-87
HNPCC Colorectal Ca Prognosis
 many
studies: stage-for-stage survival
advantage in HNPCC-CRC
landmark paper: Gryfe (NEJM 2000):
•
•
•
607 consecutive cases CRC <age 50
17% had MSI-H
Multivariate analysis showed a sigificant
survival advantage for MSI-H patients versus
MSS, independent of ALL other prognostic
factors.
The “atypical family history”
Families w multiple cases of non-CRC HNPCCassociated cancers
 *GU-TCC renal pelvis, bladder, ovarian,
squamous cell endometrial, no colorectal cancer
in “line of fire” + mutation MSH2


Are the carriers at risk of colorectal ca?
YES, and should be screened appropriately
d. 33
appendix ruptured
d. 84
5
12/20/1899
d. 49
1/16/1899
d. 49
ovarian ca; dx. 46
no info bladder ca
COD unknown
+ PA
1925
d. 59
colon ca
dx. 56
1927
80
TAH @ 41
transitional cell ca of Rt. ureter, dx. 60
Stage 1C ovarian ca, dx. 67 - tx with BSO + adjuvant chemo
peritoneal recurrence - transitional cell ca dx 74
+
28
1945
60
endometrial ca; dx. 52
MSI + IHC testing 2002 - unstable at BAT26
DNA Sequencing 2004 - MSH2 mut. +ve
27
31
34
ca, type unknown
+ PA
PA
12/17/1952
54
12/1/1931
66
pancreatic ca
dx. 68
10
1961
44
squamous cell carcinoma
dx. 38
Rt. shoulder
(Growing like keratoacanthoma)
8
34
36
d. 82
d. 62
colon ca dx. 55
uterine ca? or kidney ca?
+
d. 60
colon ca dx. 59
d. 77
colon ca dx. 77
d. stroke
d. 77
uterine ca dx. ?
MSH2 +ve
presumed MLH1 carri
4/5/1925 - ?
d. 71
colorectal ca (3 sep primaries)
dx. 55, 62, 69
1924 - ?
d. 68
stroke
?
n
1950
48
19
1956
42
MLH1 +ve
11/27/1960
38
d. 45
stroke
bowel problems
presumed MLH1 carrier
1924 - ?
d. 68
stroke
d. 64
PA
PA
1921 - ?
77
endometrial ca
dx. 53
colon ca
dx. 77
80's
colon ca
dx. 70-Toronto
PA
70-80
PA
3
1956
42
MLH1 +ve
11/27/1960
38
48
44
2
d. 48
colon ca
dx. 45
MSI unstable at Bat26 locus
IHC deficiency on MLH1
2
1987
19
11/10/1992
14
3/12/1997
10
16-25
d. 33
rectal ca
dx. 26
46
France
44
colonoscopy
2
16-25
45
3
15-21
15-21
FAP- prototype for hereditary cancer




100s to 1000s of adenomatous polyps
throughout colon & rectum
100% penetrance without surgery
Very early age of onset (polyposis by 20’s most
ca by 40s)
APC gene chromosome 5
Risk-reducing surgery in FAP


Sigmoidoscopy: q1-2 ~ age 10-12, genetic testing
Colonoscopy: once polyps + annually if colectomy is
delayed more than one year

Prophylactic Colectomy: recommended- TPC, IRA,
IPAA (ileal pouch)

Follow-up screening is necessary
JCO Oct 1, 2006 ASCO review:
FAP- Desmoids
12-17% of FAP patients
• Intra-abdominal 80%, small bowel mesentery
>50% (present w SBO)
• Genotype: APC mutation b/w codons 1310-2011
• Tend to occur AFTER surgery, high RR, high
morbidity
•
Rx: sx for small, well defined desmoids;
Tamoxifen, chemo: vinblastine, MTX (RR 4050%) or for rapidly progressive desmoids per
sarcoma protocol (adriamycin, dacarbazine)
FAP-other tumours
Upper GI tumours
• 80-90% FAP mutation carriers have duodenal
or periampullary polyps, of which
• 36% will develop advanced polyposis
• 3-5% will develop invasive carcinoma
• Surveillance: side-viewing endoscopy + bx
suspicious polyps @ 25-30 yrs
• Polypectomy for high-grade dysplasia, villous
changes, ulceration, > 1 cm size
chemoprevention?
•
•
•
NSAIDS: level 1 evidence
sulindac, celecoxib, rofecoxib shown to
reduce # polyps in FAP, but not proven to
reduce cancer incidence or mortality
** long term use as an alternative to sx is NOT
recommended + adverse effects
Calcium
HRT
FAP: natural history—revised
Due to improved diagnosis, and
prevention/screening for CRC, periampullary
cancer and desmoids have become the leading
causes of death for FAP(APC) mutation carriers
Other Polyposis Syndromes

AFAP-attenuated familial polyposis
10-100 polyps, proximal location, later age of onset
(1307K allele ~ 6% Ashkenazi Jews, 2x CRC risk)

MUTYH1 mutations: “MAP” recessive
inheritance
-7.5 % of pts w classical phenotype but APC J. Jass. Pathology Res & Practice (2008) 204: 431-447
Attenuated FAP
“MAP” MYH-associated polyposis coli
Nielsen et al, Journal of Medical Genetics 2005
Hereditary Diffuse Gastric Cancer





E-cadherin CDH1 gene
70% risk of diffuse gastric ca
40% risk of lobular breast ca
Prophylactic total gastrectomy
?screening chromoendoscopy
Lynch et al, Cancer 2008 Jun 15;112(12):2655-63
Objectives

HNPCC review
Diagnosis, genetic testing, cancer risks, risk
reduction strategies

Other Hereditary GI syndromes:
FAP, AFAP/MAP, HDGC

Criteria for referral to Familial Oncology Programs