ABSTRACT
34 35A second group of genes that plays an important role in tumorigenesis are the tumor suppressor genes. These are defined as genes involved in the control of abnormal cell proliferation and whose loss or inactivation is associated with the development of malignancy. They act therefore by effectively inhibiting or putting the brake on cell growth and cell cycling. These genes are recessive at the level of the cell although they show dominant inheritance when associated with a familiar cancer syndrome (see below). Both copies of the gene have to be mutated before tumors develop. Several dozen tumor suppressor genes have now been identified associated with human tumors (Table 3.1). Tumor suppressor genes associated with human cancers
Gene
Location
Function
Associated tumors
Familial cancer syndrome
APC
5q21
β-catenin binding, cytoskeleton stabilization, cell-cycle regulation
Colorectal
Familial adenomatous polyposis
BRCA1
17q21
DNA repair
Breast and ovarian cancer
Familial breast/ovarian cancer
BRCA2
13q12.3
DNA repair
Breast and some ovarian cancer
Familial breast/ovarian cancer
CDHI (E-Cadherin)
17q22.1
Cell adhesion
Breast, colon lung, stomach
Familial gastric cancer
CDKN1C
11 p15.5
Cyclin-dependent
Wilms’ tumor.
Beckwith-Wiedemann
(p57)
kinase inhibitor
rhabdomyosarcoma
syndrome
CDKN2A (p16)
9p21
Cell cycle
Melanoma,
Familial
CYLD
16q 12–13
regulator at G1/S
pancreatic
melanoma Familial cylindromas
EP300
22q13.2
Transcription factor-binding protein
Colorectal, breast, pancreatic
EXT1
8q24
Transmembrane glycoprotein − catalyzes polymerization of heparin sulfate
Exostoses, osteosarcomas
Multiple exostoses type 1
EXT2
11 p1 2–11
Transmembrane glycoprotein − catalyzes polymerization of heparin sulfate
Exostoses, osteosarcomas
Multiple exostoses type 2
FHIT
3p14
Lung, stomach, kidney, cervix
Familial clear cell renal cancer
MAP2K4
17p11
Protein kinase
Pancreatic, breast, colon
MEN1
11q13
Transcriptional repressor
Parathyroid, pituitary, islet cell carcinoma,
MEN1
MLH1
3p21
Mismatch repair
Colorectal
HNPCC
MLH3
14q24
Mismatch repair
Colorectal
HNPCC
MSH2
2p22
Mismatch repair
Colorectal
HNPCC
MSH6
2p16
Mismatch repair
Colorectal
HNPCC
NF1
17q 11
Regulator of RAS mediated proliferation
Neurofibromas, gliomas
Neurofibromatosis type 1
NF2
22q12
Cytoskeletal regulator and suppressor of cell adhesion
Meningiomas, schwannomas
Neurofibromatosis type 2
PMS1
2q31–3
Mismatch repair
Colorectal
HNPCC
PMS2
7p22
Mismatch repair
Colorectal
HNPCC
PRKAR1A
17q23–24
Role in cAMP pathway
Testicular, thyroid, breast ductal adenoma
Carney complex
PTCH
9q22
Regulator of sonic hedgehog
Basal cell carcinomas
Gorlin syndrome
PTEN
10q23
Protein tyrosine phosphatase
Hamartomas, prostatic, breast, endometrial
Cowdem syndrome, Bannayan–Zonana syndrome
RB1
13q14
Cell cycle inhibitor
Retinoblastomas, osteosarcomas
Familial retinoblastoma
RUNX3
Transcription factor
Gastric
SDHD
11q23
Succinate
Pheochromocytoma,
Familial
SDHC
1q21
dehydrogenase subunits
paraganglioma
paraganglioma
SDHB
1 p36–35
SMAD4
18q21
Transducer of TGFβ signals
Colorectal, pancreatic
Juvenile polyposis
SMARCB1
22q11
Regulator of chromatin
Rhabdoid tumors
STK11 (LKB1)
19q13
Serine/threonine kinase
Hamartomas, ovarian, prostate, breast
Peutz–Jegher syndrome
TP53
17p13
Transcriptional regulator
Breast, brain, colorectal, plus many more
Li–Fraumeni
TSC1
9q34
Maintainance of cytoskeleton
Brain, renal
Tuberous sclerosis
TSC2
16p13
Cell cycle regulator
Brain, renal
Tuberous sclerosis
VHL
3p26
Regulates proteolysis, responds to changes in oxygen
Renal, pheochromocytoma, hemangiomas
Von Hippel Lindau disease
WT1
11p13
Transcriptional regulator
Nephroblastoma
Wilms tumor
