Chapter17: INTESTINES:Familial Syndromes

Question 1

Familial Syndromes

Several syndromes characterized by the presence of colonic polyps and increased rates of
colon cancer have been described.

The genetic basis of these disorders has been established and has greatly enhanced our understanding of sporadic colon cancer ( Table 17-10 ).

Answer 1

• Familial adenomatous polyposis (70% of FAP)
• Familial adenomatous polyposis (<10% of FAP)
• Hereditary nonpolyposis colorectal cancer
• Sporadic colon cancer (80%)
• Sporadic colon cancer (10% to 15%)

Question 2

TABLE 17-10 – Common Patterns of Sporadic and Familial Colorectal Neoplasia

Familial adenomatous
polyposis (70% of FAP)

Answer 2

• Molecular Defect
  
  • APC/WNT
    pathway
• Target
  
  • APC
• Gene(s) Transmission
  
  • Autosomal dominant
• Predominant Site(s)
  
  • None
• Histology
  
  • Tubular, villous;
  • typical adenocarcinoma

Question 3

TABLE 17-10 – Common Patterns of Sporadic and Familial Colorectal Neoplasia

Familial adenomatous
polyposis (<10% of FAP)

Answer 3

• Molecular Defect
  
  • DNA mismatch repair
• Target
  
  • MUTYH
• Gene(s) Transmission
  
  • None,
  • recessive
• Predominant Site(s)
  
  • None
• Histology
  
  • Sessile serrated adenoma;
  • mucinous adenocarcinoma

Question 4

TABLE 17-10 – Common Patterns of Sporadic and Familial Colorectal Neoplasia

Hereditary nonpolyposis
colorectal cancer

Answer 4

• Molecular Defect
  
  • DNA mismatch repair
• Target
  
  • MSH2,
  • MLH1
• Gene(s) Transmission
  
  • Autosomal
• Predominant Site(s)
  
  • Right side
• Histology
  
  • Sessile serrated adenoma;
  • mucinous
    adenocarcinoma

Question 5

TABLE 17-10 – Common Patterns of Sporadic and Familial Colorectal Neoplasia

Sporadic colon cancer
(80%)

Answer 5

• Molecular Defect
  
  • APC/WNT pathway
• Target
  
  • APC
• Gene(s) Transmission
  
  • None
• Predominant Site(s)
  
  • Left side
• Histology
  
  • Tubular, villous;
  • typical adenocarcinoma

Question 6

TABLE 17-10 – Common Patterns of Sporadic and Familial Colorectal Neoplasia

Sporadic colon cancer
(10% to 15%)

Answer 6

• Molecular Defect
  
  • DNA mismatch repair
• Target
  
  • MSH2,
  • MLH1
• Gene(s) Transmission
  
  • None
• Predominant Site(s)
  
  • Right side
• Histology
  
  • Sessile serrated adenoma;
  • mucinous adenocarcinoma

Question 7

What are FAMILIAL ADENOMATOUS POLYPOSIS?

Answer 7

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder in which patients
develop numerous colorectal adenomas as teenagers.

It is caused by mutations of the
adenomatous polyposis coli, or APC, gene.

Question 8

What is necessary for the diagnosis of classic FAP?

Answer 8

At least 100 polyps are necessary for a diagnosis of classic FAP, and as many as several
thousand may be present ( Fig. 17-48 ).

Except for their remarkable numbers, these growths
are morphologically indistinguishable from sporadic adenomas.

In addition, however, flat or
depressed adenomas are also prevalent in FAP, and microscopic adenomas, consisting of only
one or two dysplastic glands, are frequently observed in otherwise normal-appearing mucosa.

Question 9

Answer 9

FIGURE 17-48 Familial adenomatous polyposis.

• A, Hundreds of small polyps are present throughout this colon with a dominant polyp (right).
• B, Three tubular adenomas are present in this single microscopic field.

Question 10

What develops in 100% of untreated FAP patients, often before age 30?

Answer 10

Colorectal adenocarcinoma

Question 11

What is the standard therapy for individuals carrying APC mutations?

Answer 11

prophylactic colectomy

because Colorectal adenocarcinoma develops in 100% of untreated FAP patients, often before age 30.

Colectomy prevents colorectal cancer, but patients remain at risk for neoplasia at other sites.

For example, adenomas may develop elsewhere in the GI tract, particularly adjacent to the ampulla of Vater and in the stomach.

Question 12

FAP is associated with a variety of extra-intestinal manifestations including what?

Answer 12

congenital hypertrophy of the retinal pigment epithelium, which can generally be detected at birth and can be an adjunct to early screening.

Question 13

Specific APC mutations have been associated with the
development of other manifestations of FAP and explain variants such as what?

Answer 13

Gardner syndrome and Turcot syndrome.

Question 14

What is Gardner syndrome?

Answer 14

In addition to intestinal polyps, Gardner syndrome families have:

• osteomas of mandible,
• skull, and long bones,
• epidermal cysts,
• desmoid tumors,
• thyroid tumors, and
• dental abnormalities, including unerupted and supernumerary teeth.

Question 15

What is Turcot syndrome?

Answer 15

Turcot syndrome is
rarer and characterized by intestinal adenomas and tumors of the central nervous system.

Question 16

Two thirds of patients with Turcot syndrome have APC gene mutations and develop what?

Answer 16

medulloblastomas

Question 17

What is the remaining one third of patients with Turcot syndrome have mutations in one of several genes involved in DNA repair and develop what?

Answer 17

glioblastomas

Question 18

Some FAP patients without APC loss have mutations of what?

Answer 18

base-excision repair gene MUTYH.

The role of these genes in tumor development is discussed below.

In addition,
certain APC and MUTYH mutations are associated with attenuated forms of FAP, which are characterized by delayed polyp development, the presence of fewer than 100 adenomas, and the delayed appearance of colon cancer, often to ages of 50 or above

Question 19

What is Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome?

Answer 19

, was originally described based on familial clustering of cancers at several sites including the
colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and
skin.

Question 20

​Colon cancers in HNPCC patients tend to occur at what age?

Answer 20

younger ages than sporadic colon cancers

Question 21

​Colon cancers in HNPCC patients are often located where?

Answer 21

right colon

Question 22

What is the pathogenesis of HNPCC?

Answer 22

HNPCC is caused by inherited mutations
in genes that encode proteins responsible for the detection, excision, and repair of errors that
occur during DNA replication( Chapter 7 ).

Question 23

There are at least five such mismatch repair genes,
but the majority of HNPCC cases involve what?

Answer 23

MSH2 and MLH1.

Question 24

Explain the pathogenesis of HNPCC.

Answer 24

Patients with HNPCC inherit one mutated DNA repair gene and one normal allele.

When the second copy is lost through
mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of
mutations at rates up to 1000 times higher than normal, mostly in regions containing short
repeating DNA sequences referred to as microsatellite DNA.

The human genome contains
approximately 50,000 to 100,000 microsatellites, which are prone to undergo expansion during
DNA replication and represent the most frequent sites of mutations in HNPCC.

The consequences of mismatch repair deficiency and the resulting microsatellite instability are
discussed in the context of colonic adenocarcinoma.

Question 25

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