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Hereditary syndromes that predispose individuals to cancer can be explained by the inheritance of a germline mutation (passed on from egg/

sperm DNA and thus present in all cells of an individual) in one tumor suppressor allele and the acquisition of a somatic mutation or other in-activating alteration in the second allele later in life. This was fi rst proposed by Knudson and is known as Knudson’s two-hit hypothesis. It states a strict defi nition of a tumor suppressor gene: a gene in which a germline mutation predisposes an individual to cancer. Examples of tumor sup-pressor genes that fi t this defi nition are shown in Table 6.1.

PAUSE AND THINK

Theoretically, mutation in only one allele allows the other allele to make the tumor suppressor protein and tumor suppression may still occur.

Table 6.1 Tumor suppressor genes. From Macleod, K. (2000) Tumor suppressor genes. Curr. Opin. Genet. Dev. 10: 81–93, Copyright (2000). Reprinted with permission from Elsevier

Tumor suppressor gene

Human chromosomal location

Gene function Human tumors associated with

NF1 17q11 Ras-GAP activity Neurofi bromas,

sarcomas, gliomas

Von Recklinghausen neurofi bromatosis

Pheochromocytomas, myeloid leukemia, neurofi bromas in DKO chimeras

VHL 3p25 Regulates proteolysis Hemangiomas, renal,

pheochromocytoma

Von–Hippel Lindau None

APC 5q21 Binds/regulates

β-catenin activity

Colon cancer Familial adenomatous polyposis

Intestinal polyps in Apc^Min

INK4a 9p21 p16^Ink4a cdki for cyclin D–cdk (4/6); p19^ARF binds mdm2, stabilizes p53

Melanoma, pancreatic Familial melanoma Lymphomas, sarcomas

PTC 9q22.3 Receptor for sonic

hedgehog

Breast/ovarian tumors Familial breast cancer None

BRCA2 13q12 Transcriptional

regulator/DNA repair

Breast/ovarian tumors Familial breast cancer None

DPC4 18q21.1 Transduces TGF-β

signals

Pancreatic, colon, hamartomas

Juvenile polyposis Cooperates with Apc^Δ716 in colorectal carcinoma

FHIT 3p14.2 Nucleoside hydrolase Lung, stomach,

kidney, cervical carcinoma

Familial clear cell renal carcinoma

Not reported

PTEN 10q23 Dual-specifi city

phosphatase

TSC2 16 Cell cycle regulator Renal, brain tumors Tuberous sclerosis Not reported

NKX3.1 8p21 Homeobox protein Prostate Familial prostate

carcinoma

Not reported

Although this hypothesis describes the mechanism by which mutation of most tumor suppressor genes has an effect, exceptions and additional complexities exist and will be mentioned later.

Let’s look at the breast cancer susceptibility genes BRCA1 and BRCA2 examples. Some families are prone to increased risk of develop-ing breast and ovarian cancers. The hereditary breast and ovarian can-cer susceptibility genes BRCA1 and BRCA2 are well known tumor suppressor genes that play a role in this hereditary syndrome, which make up about 5–10% of all breast cancer cases. The mechanism of these tumor suppressors follows Knudson’s hypothesis in that one ger-mline mutation predisposes individuals to breast and ovarian cancer.

The mutated genes most often produce a truncated protein and there-fore cause loss of function. Breast and ovarian tumors that develop in these individuals exhibit a loss of heterozygosity. In some cases of spo-radic (non-hereditary) breast cancer, BRCA1 protein levels are reduced, not because of mutation but rather as a result of epigenetic mechanisms.

Both BRCA proteins are involved in homologous recombination and double-strand break repair (see Figure 2.9) and therefore help maintain the integrity of the genome. They also have a role in the regulation of transcription and chromatin structure. Note, however, that there is no clear homology between BRCA1 and BRCA2. One proposal of how

LKB1 19p13 Serine/threonine

kinase

Hamartomas, colorectal, breast

Peutz–Jeghers Not reported

E-Cadherin 16q22.1 Cell adhesion regulator

Breast, colon, skin, lung carcinoma

Familial gastric cancer Dominant negative, promotes invasion/

metastasis

MSH2 2p22 mut S homolog,

mismatch repair

Colorectal cancer HNPCC Lymphoma, colon/skin carcinoma

MLH1 3p21 mut L homolog,

mismatch repair

Colorectal cancer HNPCC Lymphoma, intestinal adenoma/carcinoma

PMS1 2q31 Mismatch repair Colorectal cancer HNPCC None

PMS2 7p22 Mismatch repair Colorectal cancer HNPCC Lymphoma, sarcoma

MSH6 2p16 Mismatch repair Colorectal cancer HNPCC Lymphoma, intestinal

adenomas/carcinomas

This table does not include the susceptibility genes associated with ataxia telangiectasia (ATM/ATR), xeroderma

pigmentosum (nucleotide excision repair genes), Bloom’s syndrome (BLM), Werner’s syndrome (WRN), or Fanconi’s anemia (FAA, FAC, FAD), although mutation of these genes is associated with cancer predisposition. Nor does it include putative tumor suppressor genes which are subverted by chromosomal translocation, for example PML. Genes such as MADR2, TGF-β receptor 2, IRF-1, p73, p33^ING1, PPARγ, BUB1, and BUBR1 have been shown to be mutated in certain human tumors but are not included here because germline mutation of these genes is not yet associated with any hereditary human cancer syndrome.

BZS, Bannayan–Zonana syndrome; HNPCC, hereditary non-polyposis colorectal cancer; Ldd, Lhermitte–Duclos syndrome.

mutations in the BRCA genes cause cancer suggests that defective recombination destabilizes the genome and leads to chromosomal rear-rangements and mutation. Another proposal regarding a role for BRCA proteins in estrogen signaling is discussed in Chapter 11.

Historically, tumor suppressor genes were called “anti-oncogenes” as some of them seemed to “undo” pathways of oncogene activation.

Although the term is no longer used, it can be a helpful tool for illustrat-ing the function of some tumor suppressor genes.

The role of aberrant phosphorylation by kinases during carcinogene-sis was emphasized in Chapter 4. It is therefore predictable that some genes that encode phosphatases which antagonize kinase activity, could act as “anti-oncogenes.” Inactivation of these phosphatase genes by mutation removes the inhibitory signal and the kinase activity becomes unregulated.

One gene encoding a phosphatase that is frequently mutated in many cancers is PTEN (phosphatase and tensin homolog on chromosome 10). PTEN codes for a phosphatase with dual specifi city: it can act as both a protein and lipid phosphatase. Its role as a lipid phosphatase in oncogenesis is best known. PTEN dephosphorylates the membrane lipid PIP3 (phosphatidyl-inositol-3 phosphate) to form PIP2. This antagonizes (shown by the reversed red arrow) the PI3 kinase pathway (Figure 6.1).

Loss of the inhibitory dephosphorylation activity of PTEN in the PTEN mutant phenotype results in a constitutively active PI3 kinase pathway, involving activation of protein kinases Akt and mTOR (mam-malian target of rapamycin). The net result is the inhibition of apoptosis and induction of cell proliferation. This favors oncogenesis. Note that this gene also fi ts the tumor suppressor defi nition given earlier as a ger-mline mutation of PTEN causes Cowden syndrome which predisposes patients to cancer.

Another protein-tyrosine phosphatase, PTPN1, encoded by the PTPN1 gene, regulates tyrosine kinase receptor signaling by dephosphorylating EGFR and PDGFR. Accelerated development of lymphomas has been reported upon analysis of PTPN1 knock-out mice. Several other protein-tyrosine phosphatases also act as tumor suppressor genes.

Note that not all kinases are oncogenic and not all phosphatases are tumor suppressors. Ataxia telangiectasia mutated (ATM) kinase functions in DNA repair as mentioned in Chapter 2, and plays a role in tumor sup-pression. Many other examples exist. The role of different protein-tyrosine phosphatases as either oncogenes or tumor suppressor genes is reviewed in Ostman et al. (2006).

An examination of two “star players” in the world of tumor suppressor genes, the retinoblastoma (Rb) gene (also discussed in Chapter 5) and the PAUSE AND THINK

As kinases are enzymes that phosphorylate, what types of enzymes “undo” kinases? Phos-phatases are enzymes that remove phosphate groups.

PAUSE AND THINK

Recall that stimulation of cell membrane receptors recruits PI3 kinase to the membrane where it phosphorylates PIP2 to gener-ate PIP3, a potent second mes-senger that activates a cascade of proteins important for cell division and inhibition of apop-tosis. This signal must be tightly regulated to prevent uncon-trolled growth.

p53 gene, is central to this chapter. The roles of both gene products during carcinogenesis are described in the following sections.