Chapter 079. Cancer Genetics (Part 3) ppt

Cancer Genetics Part 3 Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition.. Roughly 100 syndromes of familial cancer have been report

Chapter 079 Cancer Genetics

(Part 3)

Familial Cancer Syndromes

A small fraction of cancers occur in patients with a genetic predisposition

In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig 79-3) Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled growth The normal function of tumor suppressors is to restrain growth, to promote differentiation (gatekeeper genes), or to preserve genome integrity (caretaker genes)

Roughly 100 syndromes of familial cancer have been reported, although many are rare The majority are inherited as autosomal dominant traits, although some of those associated with DNA repair abnormalities (xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia) are autosomal recessive Table 79-1 shows a number of cancer predisposition syndromes and the responsible genes The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types This section examines the case of inherited colon cancer in detail, but the same general lessons can be applied to all the cancer syndromes listed in Table 79-1

Table 79-1 Cancer Predisposition Syndromes and Associated Genes

Syndrome Gene Chromo

some

Inherit ance

Tumors

Ataxia

telangiectasia

ATM 11q22-q23

cancer

e

lymphoproliferativ

e syndrome

Bloom

syndrome

all types

Cowden

syndrome

PTE

N

thyroid

Familial

adenomatous

polyposis

adenoma, colorectal cancer

Familial

melanoma

p16I NK4

, pancreatic cancer

Familial

Wilms tumor

kidney cancer

Hereditary

breast/ovarian

cancer

BRC A1

BRC A2

17q21

13q12.3

ovarian, colon, prostate

Hereditary

diffuse gastric

cancer

CDH

1

cancers

Hereditary

multiple exostoses

EXT1

EXT2

8q24

11p11-12

AD Exostoses,

chondrosarcoma

Hereditary

prostate cancer

HPC

1

carcinoma

Hereditary

retinoblastoma

toma, osteosarcoma

Hereditary

nonpolyposis colon

cancer (HNPCC)

MSH

2

MLH

1

MSH

6

PMS

2

2p16

3p21.3

2p16

7p22

endometrial, ovarian, stomach, small bowel, ureter carcinoma

Hereditary

papillary renal

carcinoma

renal tumor

Juvenile

polyposis

SMA D4

stinal, pancreatic cancers

Li-Fraumeni TP53

breast cancer

Multiple

endocrine

neoplasia type 1

MEN

1

d, endocrine, pancreas, and pituitary

Multiple

endocrine

neoplasia type 2a

thyroid carcinoma, pheochromocyto

ma

Neurofibro

matosis type 1

oma, neurofibrosarcom

a, brain tumor

Neurofibro

matosis type 2

schwannoma, meningioma, spine

Nevoid

basal cell

carcinoma

syndrome (Gorlin's

syndrome)

PTC

H

9q22.3 AD Basal cell

carcinoma, medulloblastoma, jaw cysts

Tuberous

sclerosis

TSC1

TSC2

9q34

16p13.3

oma, renal angiomyolipoma

Von

Hippel–Lindau

cerebellum, pheochromocyto

ma

Note: AD, autosomal dominant; AR, autosomal recessive