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AN ORAL HISTORY OF LYNCH SYNDROME, FAP, AND

HEREDITARY DIFFUSE GASTRIC CANCER

byHENRY T. LYNCH, M.D.JANE F. LYNCH, B.S.N.

Creighton UniversitySchool of MedicineOmaha, 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 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/.

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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)Later onset (CRC ~age 50) Few colonic adenomasFew colonic adenomas Not associated with Not associated with

CHRPECHRPE UGI lesions UGI lesions Associated with Associated with

mutations at extreme 5mutations at extreme 5’’, 3, 3'' ends of ends of APCAPC gene, & exon gene, & exon 9A9A

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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 91:2598- 2601, 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*Probands Call-up pts p

CRC dx 170/252 (67%) 5/182 (3%) < 0.001CCS1 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.

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Dr. Aldred Scott WARTHIN (1866-1931)

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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 MedicineVol. 12, July-Dec., 1913

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Archives of Internal Medicine Vol. 12, July-Dec., 1913

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LYNCH SYNDROME

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Archives of Internal Medicine Vol. 117, Feb., 1966.

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24JAMA 294:2195-2202, 2005.

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Could this behereditary

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.

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Arch Intern Med 141:607-611, 1981

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Science 260:810-812, 1993.

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Genetic Heterogeneity in HNPCC

HNPCC is associated with germline HNPCC is associated with germline mutations in any one of at least five genesmutations in any one of at least five genes

Chr 2Chr 2Chr 3Chr 3

Chr 7Chr 7

MSH2MSH2

PMS1PMS1

MLH1MLH1PMS2PMS2

MSH6MSH6

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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 asecond 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

IHCSTOP(sporadic)

Hypermethylation,BRAF (V600E)

STOP(Lynch) STOP

(sporadic)

+ for MLH1

+

+ for MSH2or MSH6

mutation -mutation +

Sequencing (directed by IHC)

± MLPA(sequential or concurrent?)

Colorectal Cancer + Family History

conversion;other tumor

testing if available

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MSI/IHCSTOP(sporadic)

Hypermethylation,BRAF (V600E)

STOP(Lynch)

+ for MLH1

+ for MSH2or MSH6

mutation -mutation +

Sequencing (directed by IHC)

± MLPA(sequential or concurrent?)

Conversion;Or Linkage,

Or Testing of other tumor if available

Algorithm for Moderate/High Risk Patients (Moderate=Bethesda; High=Amsterdam II)

Colorectal Cancer + Family History,

Age < 50, etc.Syndrome X???

+

+

Stop or Test blood for

germline methylation???

STOP(Lynch)

-

STOP(other)

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HEREDITARY GASTRIC CANCER

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Historical

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Suspected stomach cancerd. age at death

Stomach cancer - macroscopic diagnosisat 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.

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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 CancerE-Cadherin Mutation CarriersNegative for E-Cadherin MutationProphylactic GastrectomyMicroscopic Foci of Early Diffuse Gastric Cancer

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Diffuse Gastric CancerE-Cadherin Mutation CarriersNegative for E-Cadherin MutationProphylactic GastrectomyMicroscopic Foci of Early Diffuse Gastric Cancer

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51HEREDITARY INTESTINAL

DIFFUSE WITH LOBULAR CARCINOMA BREAST

FAP

HNPCC

GIST

COWDEN’S SYNDROME

PEUTZ JEGHERS SYNDROME

SPORADIC

HYPERPLASTIC GASTRIC POLYPS

FAMILIAL CLUSTERING- ENVIRONMENTAL?- GENETIC?- G-E INTERACTION?

= HEREDITARY FOLLOWING MORE INTENSIVE FAMILY HISTORY

LI FRAUMENI SYNDROME

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