Genetics and Cancer

Cancer Cancer is one of the most common and severe diseases seen in clinical medicine. Statistics show that cancer in some form strikes more than one third of the population, Accounts for more than 20% of all deaths In developed countries, is responsible for more than 10% of the total cost of medical care. Cancer is invariably fatal if it is not treated. Early diagnosis and early treatment are vital, and identification of persons at increased risk of cancer before its development is an important objective of cancer research.

Sporadic Cancer Approximately 90- 95% of all cancers are sporadic and result from mutations in somatic cells Age of diagnosis typically later in life Usually not inherited As cancer is common, many patients have a fh of cancer similar to this one… having one or two fm dx with cancer in 60’s or 70’s does not increase risk as is most likely to be sporadic occurrence…. So if a patient has a fh similar to this one, you can be reassuring.

Hereditary Cancer 5-10% are inherited and caused by mutations in germline cells Several affected family members Earlier than average age of onset A particular pattern of cancers noted Individuals with more than one primary tumour site

The Genetic Basis of Cancer Regardless of whether a cancer occurs sporadically in an individual, as a result of somatic mutation, or repeatedly in many individuals in a family as a hereditary trait (germline mutation), cancer is a genetic disease. Genes in which mutations cause cancer fall into two distinct categories: oncogenes and tumor-suppressor genes (TSGs).

Oncogenes An oncogene is a mutant allele of a proto-oncogene, a class of normal cellular protein-coding genes that promote growth and survival of cells. Oncogenes facilitate malignant transformation by stimulating proliferation or inhibiting apoptosis. Oncogenes encode proteins such as: proteins in signaling pathways for cell proliferation transcription factors that control the expression of growth-promoting genes inhibitors of programmed cell death machinery

Tumor-Suppressor Genes (TSGs) Gatekeeper TSGs control cell growth. Gatekeeper genes block tumor development by regulating the transition of cells through checkpoints ("gates") in the cell cycle or by promoting programmed cell death and, thereby, controlling cell division and survival. Loss-of-function mutations of gatekeeper genes lead to uncontrolled cell accumulation. Gatekeeper TSGs encode: regulators of various cell-cycle checkpoints mediators of programmed cell death

Tumor-Suppressor Genes (TSGs) Caretaker TSGs protect the integrity of the genome. Loss of function of caretaker genes permits mutations to accumulate in oncogenes and gatekeeper genes, which, in concert, go on to initiate and promote cancer. Caretaker TSGs encode: proteins responsible for detecting and repairing mutations proteins involved in normal chromosome disjunction during mitosis components of programmed cell death machinery

Tumor Initiation Different types of genetic alterations are responsible for initiating cancer. These include mutations such as: gain-of-function mutations, including gene amplification, point mutations, and promoter mutations, that turn one allele of a proto- oncogene into an oncogene chromosome translocations that cause misexpression of genes or create chimeric genes encoding proteins with novel functional properties loss of function of both alleles, or a dominant negative mutation of one allele, of TSGs.

Tumor Progression Once initiated, a cancer progresses by accumulating additional genetic damage, through mutations or epigenetic silencing of caretaker genes that encode the machinery that repairs damaged DNA and maintains cytogenetic normality A further consequence of genetic damage is altered expression of genes that promote vascularization and the spread of the tumor through local invasion and distant metastasis.

Oncogenes Activating or gain-of- function mutations, including gene amplification, point mutations, and promoter mutations, that turn one allele of a proto-oncogene into an oncogene

Mechanisms of Activation of Proto-oncogenes Type of Gene Activated Result Regulatory mutation Growth factor genes Increased expression Structural mutation Growth factor receptors, signal-transducing proteins Allows autonomy of expression Translocation, retroviral insertion, gene amplification Transcription factors Overexpression

Activation of Oncogenes by Chromosome Translocation Oncogenes are not always the result of a DNA mutation. In some instances, a proto-oncogene is activated by a chromosome mutation, usually through translocation. More than 40 oncogenic chromosome translocations have been described, primarily in sporadic leukemias and lymphomas but also in a few rare connective tissue sarcomas. The best known example is the translocation between chromosomes 9 and 22 that is seen in chronic myelogenous leukemia (CML)

Characteristic chromosome translocations in selected human malignancies Neoplasm Chromosome Translocation Percentage of Cases Proto-oncogene Affected Burkitt lymphoma t(8;14)(q24;q32) 80%   (8;22)(q24;q11) 15% MYC t(2;8)(q11;q24) 5% Chronic myelogenous leukemia t(9;22)(q34;q11) 90%-95% BCR-ABL Acute lymphocytic leukemia 10%-15% Acute lymphoblastic leukemia t(1;19)(q23;p13) 3%-6% TCF3-PBX1 Acute promyelocytic leukemia t(15;17)(q22;q11) ∼95% RARA-PML Chronic lymphocytic leukemia t(11;14)(q13;q32) 10%-30% BCL1 Follicular lymphoma t(14;18)(q32;q21) ∼100% BCL2

Tumor Suppressor Genes The Two-Hit origin of cancer Loss of both alleles of a TSGs also play an important role in the pathogenesis of many common sporadic cancers, although in this instance, both alleles are inactivated by two somatic events occurring in the same cell.

Knudsen’s “two hit” hypothesis

Tumor Suppressor Genes The Two-Hit origin of cancer The "two-hit" model is now widely accepted as the explanation for many familial cancers besides retinoblastoma, including familial adenomatous polyposis coli, familial breast cancer, neurofibromatosis type 1 (NF1), and a rare form of familial cancer known as Li-Fraumeni syndrome.

Selected Tumor-Suppressor Genes Gene Product and Possible Function DISORDERS IN WHICH THE GENE IS AFFECTED Familial Sporadic Gatekeepers RB1 p110 Cell cycle regulation Retinoblastoma small cell lung carcinomas, breast cancer TP53 p53 Li-Fraumeni syndrome Lung cancer, breast cancer, many others DCC Decreases cell survival in the absence of survival signal from its netrin ligands None known Colorectal cancer VHL Vhl Forms part of a cytoplasmic destruction complex with APC that normally inhibits induction of blood vessel growth when oxygen is present von Hippel-Lindau syndrome Clear cell renal carcinoma Caretakers BRCA1, BRCA2 Chromosome repair in response to double-stranded DNA breaks Familial breast and ovarian cancer Breast cancer, ovarian cancer MLH1, MSH2 Repair nucleotide mismatches between strands of DNA Hereditary nonpolyposis colon cancer

Tumor Suppressor Genes The Two-Hit origin of cancer In all of these syndromes, the second hit is often but not always a mutation. Silencing due to epigenetic changes such as DNA methylation, associated with a closed chromatin configuration and loss of accessibility of the DNA to transcription factors, is another important, alternative molecular mechanism for loss of function of a TSG. Because an alteration in gene function due to methylation is stably transmitted through mitosis, it behaves like a mutation; because there is no change in the DNA itself, however, the alteration is referred to as an epigenetic rather than a genetic change. Epigenetic silencing of gene expression is a normal phenomenon that explains such widely diverse phenomena as X inactivation, genomic imprinting, and regulation of a specialized repertoire of gene expression in the development and maintenance of differentiation of specific tissues

Retinoblastoma Retinoblastoma, the prototype of diseases caused by mutation in a TSG, is a rare malignant tumor of the retina in infants, with an incidence of about 1 in 20,000 births. About 40% of cases of retinoblastoma are of the heritable form, in which the child inherits one mutant allele at the retinoblastoma locus (RB1) through the germline. A somatic mutation or other alteration in a single retinal cell leads to loss of function of the remaining normal allele, thus initiating development of a tumor. The disorder is inherited as a dominant trait because the large number of primordial retinoblasts and their rapid rate of proliferation make it very likely that a somatic mutation will occur in one or more of the more than 106 retinoblasts. The other 60% of cases of retinoblastoma are nonheritable (sporadic); in these cases, both RB1 alleles in a single retinal cell have been inactivated independently. Because two hits in the same cell is a rare event, there is usually only a single clonal tumor and the retinoblastoma is found in one eye only. Although sporadic retinoblastoma usually occurs in one place in one eye only, 15% of patients with unilateral retinoblastoma have the heritable type but by chance develop a tumor in only one eye.

Retinoblastoma LD was an otherwise healthy 9-month-old when his mother first noted that his left eye begun to turn out when he was tired. At the next routine examination, the pediatrician was not comforting, indicating to the parents that she was unable to complete her customary examination of the back of LD's left eye. A detailed ophthalmologic examination under general anesthesia revealed a single whitish elevation of the retina characteristic of retinoblastoma. Further evaluation (MRI, X-rays) showed no evidence that the tumor had spread in the orbit or had metastasized to other parts of the body. The plan was to treat LD with a course of radiation therapy. The parents were stunned to learn that their son has a cancer of the eye that  may have been inherited from one of them. LD's parents then underwent ophthalmologic examination, which indicated that neither parent was affected. A three-generation pedigree was obtained: LD's father remembers being told that he had an aunt who died in childhood after going blind, but he did not know the cause. The family history also included a paternal uncle with prostate cancer. LD has an older brother and sister, both without any signs of eye problems or other significant medical concerns.

Hereditary Cancer Syndromes Many forms of cancer have a higher incidence in relatives of patients than in the general population. There are nearly 50 mendelian hereditary cancer syndromes.

Hereditary Cancer Syndromes 6. Peutz-Jeghers syndrome 7. Phaeochromocytoma 8. Retinoblastoma 9. von Hippel-Lindau disease 10. Wilm’s tumour 1. Breast and ovarian 2. Colon Cancers 3. Li-Fraumeni Syndrome 4. Neurofibromatosis 5. Multiple endocrine neoplasia (MEN)

Familial Breast Cancer Population-based studies have shown that 9% of all women will develop breast cancer in their life time. Most cases of breast cancer are sporadic. Only 5% to 10% of all breast cancer cases are hereditary.

Familial Breast Cancer Linkage studies in families with early onset FBC led to discovery of mutations in two genes that increase susceptibility to breast and ovarian cancer; BRCA 1 on chromosome 17q21 BRCA 2 on chromosome 13q12 Together these two loci account for about ½ and 1/3 of autosomal dominant FBC . Regulation of DNA repair (double strand breaks), transcription and cell cycle.

RISKS !!! Female Male Breast Ovarian Breast Prostate BRCA1 mutation 40-87% 16-63% ? 25% BRCA2 mutation 28-84% 27% 6-14% 20% General population 8-10% 1.5% <0.1% 10

Familial Colon Cancer 1.Familial adenomatous polyposis (FAP) 15% of colon cancers APC gene (TSG) on chromosome 5q APC regulates transcription, cell adhesion, apoptosis and cell proliferation. Both alleles of APC must be inactivated for adenoma formation.

Familial Colon Cancer 2. Hereditary Nonpolyposis Colon Cancer 2-4% of colon cancers Mutations on 6 DNA mismatch repair genes (MLH1, MSH2,MSH6, MLH3, PMS1, PMS2) Both alleles of genes must lose function. Male heterozygotes for mutant HNPCC genes 90% lifetime risk for development of colon cancer Female heterozygotes 70%, but 40% for endometrial cancer

Li-Fraumeni Syndrome There are rare "cancer families" in which there is a striking history of many different forms of cancer (including several kinds of bone and soft tissue sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma), affecting a number of family members at an unusually early age, inherited in an autosomal dominant pattern. This highly variable phenotype is known as the Li- Fraumeni syndrome (LFS).

Li-Fraumeni Syndrome TP53, encoding the protein p53, is inactivated in the sporadic forms of many of the cancers found in LFS, TP53 was considered a candidate for the gene defective in LFS. DNA analysis of several families with LFS has now confirmed this hypothesis; affected members in more than 70% of families with LFS carry a mutant form of the TP53 gene as a germline mutation. The p53 protein is a DNA-binding protein that appears to be an important component of the cellular response to DNA damage.

p53 suppresses progression through the cell cycle in response to DNA damage initiates apoptosis if the damage to the cell is severe acts as a tumour suppressor is a transcription factor and once activated, it represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an inherited condition that puts people at an increased risk for developing hamartomatous polyps in the digestive tract, as well as breast, colorectal, and other types of cancer. The STK11 gene (also known as the LKB1 gene) is the only gene that has been linked to PJS so far.

Neurofibromatosis Neurofibromatosis (NF) is caused by mutation in the neurofibromin gene AKA von Recklinghausen disease , Watson disease An autosomal dominant neurogenetic disorder Characterized by the presence of multiple benign neurofibromas Affects the bone, the nervous system, soft tissue, and the skin Clinical symptoms increase over time Neurologic problems and malignancy may develop

Genotype/Phenotype Increased concentrations of nerve growth stimulating activity have been linked with the development of neurofibromatosis NF-1 is a disorder with variable phenotypic expression Some patients may mainly have cutaneous expression, and others may have life-threatening or sever disfigurement The variation of this disease is even shown within families The spontaneous mutation rate is 100 times greater than for many genes, and it is thought to contribute to approximately 30- 50% of neurofibromatosis cases. A genotype- phenotype analysis suggests that there is no clear relationship between specific NF1 mutations and clinical features of Neurofibromatosis type 1.

Diagnostic criteria for NF-1 (The diagnostic criteria are met if 2 or more of the features listed are present.) Six or more café au lait macules larger than 5 mm in greatest diameter in prepubertal individuals and those larger than 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis A first-degree relative with NF-1 according to the above criteria

Colorectal Cancer 11% of cancer- related deaths Tumor progression may take 10-35 years Adenomatous polyp develops into carcinoma