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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
                                                               2



             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 first-
   degree 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/.
                               3




Family History, Cancer Risk,
      and Diagnosis
                                                             4


          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.
                                                      5



         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.
                                                  6



        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.
                                                           7

       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.
                                                       8

       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.
                                                         9



                  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.
                                                         10


                   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.
                                   11


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
                 12




Gastric Cancer
                                                    13



      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 91:2598-
 2601, 1996.
                                                   14



        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.
                                                                      15

          The Danish Polyposis Registry*
              Probands              Call-up pts          p
CRC dx        170/252 (67%)         5/182 (3%)        < 0.001
CCS1          44%                   94%               < 0.0001
___________________________________________________________________

                  <1975             1976-2001           p
CRC prevalence       60%              27%            < 0.0001
colectomy use        52%              93%            < 0.00001
 CCS1 in FAP with time:                             < 0.00001
Conclusion: Registry participation likely main cause of
 in CCS1.
1CCS  = cumulative crude survival
*Bülow. Gut 52:742-746, 2003.
                                       16




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.”

                                         17
Archives of Internal Medicine
  Vol. 12, July-Dec., 1913
                                18
                                                         19
Archives of Internal Medicine Vol. 12, July-Dec., 1913
LYNCH SYNDROME




                 20
Archives of Internal Medicine Vol. 117, Feb., 1966.
                                                  21
22
23
JAMA 294:2195-2202, 2005.
                            24
Could this be
 hereditary
Colon Cancer




                25
26
                                           27
    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




                                    28
Science 260:810-812, 1993.


                             29
                                                 30




 Genetic Heterogeneity in HNPCC

         MSH6
                         MLH1
         MSH2
                                         PMS2


         PMS1
                                 Chr 7
                 Chr 3
 Chr 2
HNPCC is associated with germline mutations in
       any one of at least five genes
                                                 31



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.
                                                                                      32

     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;
                                                                                            33


      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.
                                                                                               34
           Algorithm for Population Screening
                                                Colorectal Cancer
                                                 + Family History



                    STOP                  -           IHC
                  (sporadic)

                                                                    + for MLH1
                                     + for MSH2
                                      or MSH6
         Sequencing
       (directed by IHC)                               -                   Hypermethylation,
            ± MLPA                                                          BRAF (V600E)
   (sequential or concurrent?)
mutation   +                     mutation   -
                                                                                       +
                          conversion;
       STOP               other tumor
      (Lynch)                 testing                                              STOP
                           if available                                          (sporadic)
Algorithm for Moderate/High Risk Patients                                                                      35


(Moderate=Bethesda; High=Amsterdam II)
                                                Colorectal Cancer
                                                + Family History,
 Syndrome X                                       Age < 50, etc.
    ???


                    STOP                 -           MSI/IHC
                  (sporadic)

                                                                    + for MLH1
                                     + for MSH2
                                      or MSH6
         Sequencing
       (directed by IHC)                               -                      Hypermethylation,
            ± MLPA                                                             BRAF (V600E)
   (sequential or concurrent?)
mutation   +                     mutation   -                                    +
                                                                                    Stop or
                                                                                 Test blood for
                            Conversion;                                       germline methylation
       STOP                 Or Linkage,                                               ???
      (Lynch)            Or Testing of other                                    -               +
                          tumor if available
                                                                    STOP                              STOP
                                                                    (other)                          (Lynch)
                     36




HEREDITARY GASTRIC
     CANCER
             37
Historical
                                         38




Suspected stomach cancer
d. age at death
Stomach cancer - macroscopic diagnosis
at autopsy or per physician report
 Napoleon Bonaparte
                                                39

     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).
                                                               40

            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.
                                                        41

         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.
                                                                   42

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.
                                                      43
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.
                                                        44


          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.
                                             45



      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.
                                                   46




Diffuse Gastric Cancer
E-Cadherin Mutation Carriers
Negative for E-Cadherin Mutation
Prophylactic Gastrectomy
Microscopic Foci of Early Diffuse Gastric Cancer
                                                   47




Diffuse Gastric Cancer
E-Cadherin Mutation Carriers
Negative for E-Cadherin Mutation
Prophylactic Gastrectomy
Microscopic Foci of Early Diffuse Gastric Cancer
48
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50
           HEREDITARY INTESTINAL                       51

             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
52

				
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