Transcript HNPCC-FAP-9 - People at Creighton University

1
CANCER GENETICS:
IDENTIFICATION AND
MANAGEMENT OF INDIVIDUALS
WITH LYNCH SYNDROME
HENRY T. LYNCH, MD
Creighton University
School of Medicine
Omaha, Nebraska
Hereditary Cancer Syndromes:
Nuts and Bolts
• Family history;
•
•
•
•
•
•
•
Hereditary cancer syndrome diagnosis;
Genetic counseling;
DNA studies;
Highly targeted surveillance/management;
Extend to all at-risk relatives;
Physician education;
Research problem of discrimination (insurance,
employment);
• Strategies for wide-spread interest of familial
cancer approach to cancer control, malpractice,
molecular genetics, other.
2
3
Patient’s Modified Nuclear Pedigree
Why Pursue Cancer of All Anatomic Sites?
Pertinent for any hereditary cancer syndrome diagnosis;
Most identified by pattern of cancer expression, e.g.:
• breast and ovary (HBOC syndrome);
• CRC, endometrium, ovary, others (Lynch syndrome);
• sarcomas, breast, brain, multiple others in SBLA (LiFraumeni syndrome);
• medullary thyroid carcinoma and
pheochromocytoma (MEN-2a and MEN-2b);
• melanoma and pancreatic cancer with CDKN2A
(p16) mutation (FAMMM syndrome);
• diffuse gastric cancer and lobular breast cancer
with CDH1 mutation (HDGC syndrome);
6
...and the list goes on.
7
Colorectal Cancer
Worldwide estimates for colorectal cancer during 2008*:
Incidence – 1,233,711
Mortality –
608,644
Worldwide estimates for familial/hereditary CRC during
2008*:
Lynch syndrome 3-5% of all CRC
37,011-61,686
FAP
<1% of all CRC
<12,337
Familial
20% of all CRC
246,742
*GLOBOCAN. The International Agency for Research
on Cancer web site. URL: http://www.iarc.fr/
8
Familial/Hereditary CRC in US
Annual CRC incidence in US: 142,570
Lynch syndrome 3-5% of all CRC
4,277 - 7,129
FAP
<1% of all CRC
<1,426
Familial
20% of all CRC
28,514
Jemal et al. CA Cancer J Clin 60:277-300,2010.
8
9
Magnitude of the Problem
Question: Why are these figures of such
significant public health impact?
Answer: Each hereditary cancer comes from a
family that could benefit immensely from genetic
counseling.
DNA testing, surveillance, and highly-targeted
management are the key!
Genetic Counseling
• Mandatory
• Centers of Cancer Genetic Expertise
• Physician Role, unfortunately, often
insufficient
10
11
Should we test all
colorectal cancer for
Lynch Syndrome?
YES! Test everybody.
12
Search for LS Among CRC Affecteds*
Evidence:
Among 500 CRC patients, 18 (3.6%) had LS.
Of these 18:
 18 (100%) had MSI-H CRCs;
 17 (94%) were correctly predicted by IHC;
 only 8 (44%) were dx < 50 years;
 only 13 (72%) met the revised Bethesda guidelines;
 1/35 cases of CRC show LS.
*Hampel et al. J Clin Oncol 26:5783-5788, 2008.
13
Molecular Genetic Screening for LS
Recommendation*:
All incident CRC and EC cases should be molecularly
screened for LS.
MSI highly sensitive (89.3%).
IHC equally sensitive (91.2%), is inexpensive, is more
readily available, and predicts the nonworking gene.
IHC is preferred method to screen for LS*.
*Hampel et al. J Clin Oncol 26:5783-5788, 2008.
14
Cost-effectiveness of DNA Testing
Estimate the cost-effectiveness of genetic testing
strategies to identify LS among newly dx CRC
patients using MSI and IHC.*
Conclusion:
Preliminary tests seem cost-effective from the U.S.
health care system perspective.
Detects nearly twice as many cases of LS as
targeting younger patients.
MMR testing is not cost effective.
*Mvundura et al. Genet Med 12:93-104, 2010.
Familial CRC Type “X”
Amsterdam Criteria positive but lacking MSI and MMR
mutations will constitute ~ 40% of those AC-I without MMR
mutations and therein referred to as familial CRC type X.*
1) CRC > left side
2)  CRC and extra colonic CRC
3) Later age CRC onset
4) Molecular genetics (MSI and IHC or MMR
mutation) ABSENT!
*Lindor et al. JAMA 293:1979-1985, 2005.
15
16
Screening for Amsterdam Criteria LS*
a) Screening of all CRC patients meeting Amsterdam
Criteria (AC) would fail to detect half of all cases;
b) Screening those aged 50 would detect only
half of all cases;
c) Screening of all patients using Bethesda
Guidelines for MSI would fail to detect at least
1/3 of all cases.
*Boland & Shike. Gastroenterology 138:2197.e12197.e7, 2010.
Familial CRC
Familial clustering of CRC, like that for carcinoma of
the breast and stomach, has been discussed for more
than 100 years.
What does it mean from the standpoint of risk?
Best answer – First- degree relative of CRC
affected has 2-3 fold excess risk for CRC
compared to population expectations.
But is type X different?
Answer – Risk remains elusive!
17
18
Mismatch Repair (MMR) Mutations
Genetic Heterogeneity in HNPCC
MSH6
MSH2
MLH1
PMS2
PMS1
Chr 7
Chr 3
Chr 2
HNPCC is associated with germline mutations in
any one of at least five genes
19
Cardinal Features of Lynch Syndrome
• Family pedigree shows autosomal dominant inheritance pattern
for syndrome cancers.
• Proximal (right-sided) CRC predilection: 70-85% of Lynch syndrome CRCs
are proximal to the splenic flexure.
• Earlier average age of CRC onset than in the general population:
- Lynch syndrome: 45 years;
- general population: 63 years.
• Accelerated carcinogenesis, i.e., shorter time for a tiny adenoma to develop
into a carcinoma:
- Lynch syndrome: 2-3 years;
- general population: 8-10 years.
• High risk of additional CRCs:
25-30% of patients who have surgery for a LS-associated CRC will
have a second primary CRC within 10 years, if surgery was < a
subtotal colectomy.
Increased risk for certain
extracolonic malignancies











20
Endometrial
Ovary
Stomach
Small bowel
Pancreas
Liver and biliary tree
Muir-Torre cutaneous features
Brain, (glioblastoma) – Torre syndrome features
Prostate cancer
Breast
Possible Adrenal cortical carcinoma and others.
Cardinal Features of Lynch Syndrome
• Differentiating pathology features of LS CRCs:
- more often poorly differentiated;
- excess of mucoid and signet-cell features;
- Crohn’s-like reaction;
- significant excess of infiltrating lymphocytes
within the tumor.
• Increased survival from CRC.
• Sine qua non for diagnosis is identification of
germline mutation in MMR gene (most commonly
MLH1, MSH2, MSH6) segregating in the family.
21
22
COLONOSCOPY
 Initiate age 20 – 25
 every other year to age 40; annually thereafter
 must get good cleanout and visualize cecum
 CRC – need subtotal colectomy
23
EC Screening
Effectiveness of screening for EC is unproven;
Consequently, prophylactic surgery is the best option
for ♀ who have completed their families.*
*Manchanda et al. Curr Opin Obstet Gynecol
21:31-38, 2009.
24
Screening for EC in LS*
No screening tool has been validated.
Ultrasonography (US) used to screen for atypical
hyperplasia and cancer.
Considered normal if no polyps or intrauterine
abnormalities seen and if maximum endometrial
thickness < 4mm in postmenopausal ♀ on hormonal
replacement therapy or < 6mm in other ♀.
*Lécuru et al. Int J Gynecol Cancer 20:583-587, 2010.
25
N Engl J Med 354: 261-269, 2006.
26
27
28
Could this be
hereditary
Colon Cancer
Targeted CRC Screening
Screening is melded to LS’s natural history:
Proximal location  colonoscopy
Early age of onset  beginning at age 25
Accelerated carcinogenesis  every 1-2 yrs < age 40,
then annually
Pattern of extracolonic cancers  targeted screening
29
30
Dis Colon Rectum 53:77-82, 2010.
31
Extended Colectomy*
Continued:
Times to subsequent CRC and subsequent abdominal
surgery were significantly shorter in the control group (P <
.006 and P < .04, respectively).
No significant difference in survival time between the cases
and controls.
Conclusion: Even though no survival benefit the increased
incidence of metachronous CRC and increased abdominal
surgeries among controls warrant subtotal colectomy in
patients with LS.
*Dis Colon Rectum 53:77-82, 2010.
32
Cancer Control 16:14-22,2009.
33
Meyer et al. Cancer Control 16:14-22,2009.
34
J Clin Pathol 62:679-684, 2009.
35
J Clin Pathol 62:679-684, 2009.
36
J Clin Pathol 62:679-684, 2009.
37
Familial
Hereditary
AC-1 without MMR
(Familial CRC of
syndrome “X”)
Sporadic
TACSTD1 (EPCAM)
FAP; AFAP
Mixed Polyposis Syndrome
Ashkenazi I1307K
CHEK2 (HBCC)
MUTYH (MAP)
TGFBR1
PJS
FJP
CD
BRRS
Hamartomatous
Polyposis
Syndromes
= as yet undiscovered
hereditary cancer variants
38
Hereditary Polyposis
Syndromes
39
40
Attenuated FAP

Later onset (CRC ~age 50)

Few colonic adenomas

Not associated with
CHRPE

UGI lesions

Associated with
mutations at extreme 5’, 3'
ends of APC gene, & exon
9A
41
42
Molecular Diagnosis of LS: Toward a
Consensus
If tumor is MSI-positive, IHC is then done to direct
mutational testing to a specific MMR gene, which MSI
alone cannot do.*
If tumor is MSS, must weigh low probability of an
informative IHC test and cost of performing it.**
*Engel et al. Int J Cancer 118:115-122, 2006.
**Lynch et al. J Natl Cancer Inst 99:261-263, 2007.
43
BRAF V600E mutation and LS
BRAF V600E mutation can sort this out
since when detected it excludes LS and
contributes to improved costeffectiveness of genetic testing for LS.
*Clin Gastroenterol Hepatol 6:206-214, 2008.
MORPHOLOGY
SUSPICIOUS
FOR MSI-H
Run PCR test
for MSI status
Is there
MSI-H?
NO
FAMILIAL CRC
TYPE “X”
NO
YES
Is there loss
of staining
with any of
the Abs?
Run mutation analysis
for BRAF V600E
Is there
BRAF V600E
mutation?
NO EVIDENCE OF
LYNCH
SYNDROME
NO
IHC for MLH1,
MSH2, MSH6, PMS2
YES
PUTATIVE
LYNCH
SYNDROME
MMR GENES MUTATION
ANALYSIS
YES
SPORADIC CRC
WITH MSI-H
NO
Is there
a mutation in MMR
gene?
YES
Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26
LYNCH
SYNDROME
44
45
Frequency of MMR Mutations*
~60% of Amsterdam+ families with clinically defined
LS phenotype carry point mutations or large genomic
deletions in the transcription of either MLH1 or MSH2
genes.
Conversely, the pathogenic change inactivating the
MMR system is not known or not fully understood in
the remaining ~40%.
*Lagerstedt-Robinson et al. J Natl Cancer Inst
99:291-299, 2007.
46
Frequency of MMR Mutations*
A portion of this ~40% lacking MMR mutations is
caused by a mutation mechanism in the gene
known as EPCAM.
Others have been classified as familial colorectal
cancer Type “X”.**
*Kovacs et al. Hum Mutat 30:197-203, 2009.
**Lindor et al. JAMA 293:1979-1985, 2005.
47
Epithelial Cell Adhesion Molecule (EPCAM)
Gene and Its Lynch Syndrome Connection
Diagnosis
Genetic Counseling
Impacts
Phenotype site specific CRC
Pathogenesis
Pharmacogenetics
5’ EPCAM deletion
Exons 8 and 9 and polyadenylation sequence
Polyadenylation Sequence
Transcriptional read through
Hypermethylation of the MSH2 promoter
Ligtenberg MJ, Nature Genetics 2009.
48
49
Why LS with Site-Specific CRC?
Deletion in EPCAM results in hypermethylation
and incomplete silencing of MSH2.
EPCAM mutation carriers may have phenotypic
features that differ from carriers of MSH2
mutations – namely, an almost exclusive
expression of site-specific CRC, thereby lacking
extracolonic cancers.
50
American and Dutch families have the same
deletion in the EPCAM gene
MSH2
EPCAM
Deletion
c.859-1462_*1999del
(4.9 kb, starting in intron 7
and including exons 8 & 9)
Lightenberg, Nature Genetics 2009.
51
History of Family R*
Ascertained by us in 1970 and followed continuously.
700 blood line relatives
327 individuals age ≥ 18, ≥ 25% pedigree risk
Phenotype strikingly similar to LS but integral extracolonic
cancers absent (site-specific CRCs)
*Lynch et al. Cancer 56:934-938, 1985.
Lynch et al. Cancer 56:939-951, 1985.
First patient identified with
EPCAM mutation
CRC affecteds
EPCAM results
52
53
American and Dutch EPCAM mutations
originate from a common ancestor
Family R and the Dutch families share a 6.1 MB region surrounding
the same EPCAM deletion indicating a common ancestor. Based on the size of the
shared region it is estimated the deletion occurred 10 generations ago.
Chromosome 2
Chromosome 2
Deletion and Region
inherited from
common ancestor
Dutch Families
Family R
54
J Clin Oncol25:3534-3542, 2007.
55
Who Should Be Tested?
1. Pedigree consistent with hereditary colorectal
cancer (CRC) syndrome;
2. Known germline mutation predisposing to
cancer;
3. Patients at acceptable high cancer risk status;
4. Presence of cancer syndrome stigmata
(phenotype): e.g., polyposis in FAP;
5. Genetic counseling, risks/benefits understood;
6. Consent given;
7. Results: full explanation of
surveillance/management advice.
56
Family Information Service (FIS)
Cost-effective and highly efficient way of
educating and counseling all available family
members from a geographic catchment area
during a single setting.
Makes best use of physician’s time and effort,
has group therapy potential and patients
welcome it.
57
58
59
Conclusions for EPCAM
Conclusions:
1) Cancer control compliance in Family R profound;
2) 40% of AC-I cases lack MMR mutations – how
many may qualify as EPCAM?
3) Likely EPCAM phenotype site-specific CRC;
4) What can we learn from molecular features of
EPCAM for pharmacologic benefit?
5) 1/35 CRC affecteds likely LS (Hampel et al.*).
*J Clin Oncol 26:5783-5788, 2008.
60
Personalized Medicine
Patients
Need Individual management
based upon Genetic diagnosis
(deleterious mutation helpful)
Physicians
Need more clinical
genetic education.
Example: multiple
polyps = FAP;
multiple primary
cancer pattern =
syndrome
identification
What is advantage of
extensive family
history; genetic
counseling; genetic
testing (MMR, MSI,
IHC, BRCA1/2);
screening?
Payers
61
62
J Clin Pathol 62:679-684, 2009.