Download Hereditary Diffuse Gastric Cancer

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AN ORAL HISTORY OF LYNCH
SYNDROME, FAP, AND
HEREDITARY DIFFUSE GASTRIC
CANCER
by
HENRY T. LYNCH, M.D.
JANE F. LYNCH, B.S.N.
Creighton University
School of Medicine
Omaha, Nebraska
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Magnitude of the Problem
Annual worldwide incidence of CRC is 1,023,152*:
• Lynch syndrome (LS) accounts for  2-5%
(20,460-51,160 cases).
• < 1% (10,230 cases) constitute FAP.
•  20% (204,630 cases) are familial (2 or more firstdegree relatives with CRC.
• Each family is a cancer prevention target!
*International Agency for Research on Cancer. Globocan 2002.
Available at: http://www-dep.iarc.fr/.
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Family History, Cancer Risk,
and Diagnosis
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History of Hereditary Cancer
History of FAP:
Historical review detailed by Bussey*.
Menzelio** (1721) - first example of patient with large
number of polyps in GI tract.
Cripps*** (1882) reported polyposis in 2 members of
same family; likely first indication that it was familial.
*Familial Adenomatous Polyposis. New York: Alan R.
Liss Inc., 1990, pp. 1-7.
**Ast Med Berolinensium 4:68-71, 1721.
***Trans Pathol Soc London 33:165-168, 1882.
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History of Hereditary Cancer
History of FAP (continued):
Bickersteth* (1890) reported a family with affected
members in 2 generations (mother and son).
Smith** (1887) “adenocarcinoma” of colon in 3
members of a family with multiple polyps.
*Hosp Rep 26:299-301, 1890.
**St Bartholomew’s Hos Rep 23:225-229, 1887.
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History of Hereditary Cancer
St. Mark’s Hospital and Cancer Registry:
Cuthbert Dukes, consultant pathologist at St.
Mark’s, pioneered family studies, importance of
pedigree.
FAP Registry at St. Mark’s established 1925.
Polyp registry for all varieties of polyposis
syndromes.
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Associated Extracolonic Lesions
Gardner and Richards (1953) published a polyposis
family with the following:
• multiple osteomas of the cranium and mandible;
• multiple epidermoid cysts;
• fibromas of the skin;
Subsequently called Gardner’s syndrome.
Additional findings in same family:
• dental abnormalities (supernumerary teeth);
• desmoid tumors of the abdominal wall;
• extension of osteomas to any part of skeletal system.
*Am J Hum Genet 5:139-147.
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Associated Extracolonic Lesions
Also associated with FAP:
• congenital hypertrophy of the retinal pigment
epithelium (CHRPE);
• gastric polyps (adenomas and fundic gland polyps);
• extracolonic carcinomas:
• stomach,
• duodenum,
• jejunum,
• pancreas,
• bile duct,
• papillary thyroid carcinoma,
• hepatoblastoma.
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History of FAP
Chromosome 5 and APC mutation:
Herrera et al* (1986) identified interstitial deletion
of chromosome 5 in patient with multiple
developmental abnormalities and colonic polyps.
Bodmer et al** (1987) gave evidence for APC
mutation on chromosome 5.
*Am J Med Genet 25:473-476.
**Nature 328:614-616.
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History of FAP
Attenuated FAP:
Lynch et al* (1988) reported a cancer-prone family with
a few adenomas, autosomal dominant, described
initially as hereditary flat adenoma syndrome.
Spirio et al. (1992**- 1993***) linked this family and
others with similar phenotypes to chromosome 5q
(APC locus).
*J Natl Cancer Inst 80:278-282.
**Am J Hum Genet 51:92-100.
***Cell 75:951-957.
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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
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Gastric Cancer
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Associated Extracolonic Lesions
Desmoids
Difficult and dangerous to manage.
While not cancer, they extend and obstruct vital
anatomic structures.
Surgery may provoke desmoid formation*.
*Lynch & Fitzgibbons. Am J Gastroenterol 91:25982601, 1996.
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History of Hereditary Cancer
Unacceptable mortality in FAP:
Arvanitis et al. at Cleveland Clinic showed that
59% of patients with FAP in 1990 were dying of
metastatic CRC.*
Employment of FAP Registries** is helping to
reduce mortality!
*Dis Colon Rectum 33:639-642, 1990.
**Int J Clin Oncol 9:308-316, 2004.
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The Danish Polyposis Registry*
CRC dx
CCS1
Probands
170/252 (67%)
44%
Call-up pts
5/182 (3%)
94%
p
< 0.001
< 0.0001
___________________________________________________________________
<1975
CRC prevalence
60%
colectomy use
52%
 CCS1 in FAP with time:
1976-2001
27%
93%
p
< 0.0001
< 0.00001
< 0.00001
Conclusion: Registry participation likely main cause of
 in CCS1.
1CCS
= cumulative crude survival
*Bülow. Gut 52:742-746, 2003.
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Dr. Aldred Scott WARTHIN (1866-1931)
Aldred Scott Warthin, M.D., Ph.D.
(1866-1931)
A distinguished portion of his achievement
centers on the relationship between cancer and
genetics, which predated the rediscovery of
Mendel’s principles and opened the question of
cancer-prone families for modern study. He
can properly be called “The Father of Cancer
Genetics.”
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Archives of Internal Medicine
Vol. 12, July-Dec., 1913
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Archives of Internal Medicine Vol. 12, July-Dec., 1913
LYNCH SYNDROME
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Archives of Internal Medicine Vol. 117, Feb., 1966.
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JAMA 294:2195-2202, 2005.
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Could this be
hereditary
Colon Cancer
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First Lynch Syndrome Family in South
America, published by my colleague
Carlos Sarroca*
Cancer colonico familiar sin poliposis:
enfoque clinico y anatomopatologico.
Perspectivas de estudio genetico.
C. Sarroca, WA. Ferreira, R. Quadrelli
Cir del Uruguay 47:515-520, 1977.
Arch Intern Med 141:607-611, 1981
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Science 260:810-812, 1993.
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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
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Lynch Syndrome: Genotypic Heterogeneity
Clinical cancer phenotypes differ with each of
the MMR mutations:
1. MSH2 has  extracolonic cancer types and
 Muir-Torre syndrome
2. MLH1 may have  CRC expression.
3. MSH6 may be more “benign” with  CRC but
 endometrial cancer.
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Cardinal Features of Lynch Syndrome
• Family pedigree shows autosomal dominant inheritance pattern for syndrome
cancers.
• 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:
- endometrium (40-60% lifetime risk for ♀ carriers);
- ovary (12% lifetime risk for ♀ carriers);
- stomach (higher risk in families from Orient);
- small bowel;
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Cardinal Features of Lynch Syndrome
•
Increased risk for certain extracolonic malignancies (continued):
- hepatobiliary tract;
- pancreas;
- upper uroepithelial tract (transitional cell carcinoma of the ureter and renal
pelvis);
- brain (in Turcot’s syndrome variant of LS);
- sebaceous adenomas, sebaceous carcinomas, multiple keratoacanthomas
(in Muir-Torre syndrome variant of LS).
• 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.
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Algorithm for Population Screening
Colorectal Cancer
+ Family History
STOP
(sporadic)
IHC
+ for MLH1
+ for MSH2
or MSH6
Sequencing
(directed by IHC)
± MLPA
(sequential or concurrent?)
mutation
+
Hypermethylation,
BRAF (V600E)
mutation
-
+
STOP
(Lynch)
conversion;
other tumor
testing
if available
STOP
(sporadic)
Algorithm for Moderate/High Risk Patients
(Moderate=Bethesda; High=Amsterdam II)
Colorectal Cancer
+ Family History,
Age < 50, etc.
Syndrome X
???
STOP
(sporadic)
MSI/IHC
+ for MLH1
+ for MSH2
or MSH6
Sequencing
(directed by IHC)
± MLPA
(sequential or concurrent?)
mutation
+
STOP
(Lynch)
Hypermethylation,
BRAF (V600E)
mutation
-
+
Stop or
Test blood for
germline methylation
???
Conversion;
Or Linkage,
Or Testing of other
tumor if available
STOP
(other)
+
STOP
(Lynch)
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HEREDITARY GASTRIC
CANCER
Historical
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Suspected stomach cancer
d. age at death
Stomach cancer - macroscopic diagnosis
at autopsy or per physician report
Napoleon Bonaparte
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Familial Gastric Cancer: Lynch
Syndrome
• GC incidence shows large geographic
differences worldwide in Lynch syndrome.
• Lowest rates in most Western industrialized
countries.
• Relatively high rates of GC occur in Lynch
syndrome in Japan, Korea, China, and South
America (particularly Chile).
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Familial Gastric Cancer
• Intestinal type:
• More common in general population;
• More likely to be sporadic and related to environmental
factors such as diet, particularly salted fish and meat,
smoked foods, cigarette smoking, and alcohol use;
• Pathology - Components of glandular, solid, or
intestinal architecture, as well as tubular structures;
• H. pylori infection a risk for intestinal type with lesser
involvement in diffuse type.
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Hereditary Gastric Cancer
• Intestinal type has shown a worldwide decline
in incidence; DGC remains stable and may
even be increasing.
• Diffuse gastric cancer (DGC) is more often
described etiologically with host factor effects.
• *Lynch et al. J Surg Oncol 90:114-133, 2005.
• **Crew & Neugut. World J Gastroenterol 12: 354-362,
2006.
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Hereditary Diffuse Gastric Cancer (HDGC)
 5-10%
of gastric cancer is familial, and between 1-3% is
hereditary.*
• Historically, Guilford et al.*** described the truncating CDH1
germline mutations accounting for HDGC in 3 Maori families,
showing autosomal dominant inheritance of this disease.
• It is estimated that  30-40% of HDGC families harbor
E-cadherin (CDH1) germline mutations.**
*Lynch et al. J Surg Oncol 90:114-133, 2005.
**Caldas et al. J Med Genet 36:873-880, 1999.
***Nature 392:402-405, 1998.
Hereditary Diffuse Gastric Cancer (HDGC)
• Hereditary diffuse gastric cancer (HDGC) first
reported in 1964*.
• In this original Maori kindred, a descendant died
at age 14 and > 25 of his relatives have died of
cancer**.
• Guilford et al. first described E-cadherin (CDH1)
germline mutations in HDGC in 1998**.
• *Jones. N Z Med J 63:287-296, 1964.
• **Guilford et al. Nature 392:402-405, 1998.
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Familial Gastric Cancer
• Diffuse type:
• More likely primary genetic etiology;
• A subset (HDGC) due to E-cadherin (CDH1)
germline mutation;
• Pathology - poorly cohesive clusters, signet cells
which infiltrate the gastric wall, widespread
thickening and rigidity (linitus plastica);
• Differential diagnosis, as in most hereditary forms
of cancer, shows significant heterogeneity.
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CDH1 Mutations and HDGC
• This knowledge has impacted heavily
upon the care of HDGC families.
• Surveillance has not been effective.
• Prophylactic total gastrectomy has
lifesaving potential*.
• *Lewis et al. Surgery 130:612-619, 2001.
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Diffuse Gastric Cancer
E-Cadherin Mutation Carriers
Negative for E-Cadherin Mutation
Prophylactic Gastrectomy
Microscopic Foci of Early Diffuse Gastric Cancer
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Diffuse Gastric Cancer
E-Cadherin Mutation Carriers
Negative for E-Cadherin Mutation
Prophylactic Gastrectomy
Microscopic Foci of Early Diffuse Gastric Cancer
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HEREDITARY INTESTINAL
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DIFFUSE WITH LOBULAR CARCINOMA BREAST
FAP
HNPCC
GIST
COWDEN’S SYNDROME
LI FRAUMENI SYNDROME
PEUTZ JEGHERS SYNDROME
HYPERPLASTIC GASTRIC POLYPS
FAMILIAL CLUSTERING
- ENVIRONMENTAL?
- GENETIC?
- G-E INTERACTION?
SPORADIC
= HEREDITARY
FOLLOWING MORE
INTENSIVE FAMILY
HISTORY
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