Cancer and genetic Cancer and genetic influencesinfluences 1. overview & oncogenes1. overview & oncogenes

Lec 24Lec 24

What is cancer?What is cancer?A name used to describe a form of A name used to describe a form of neoplasianeoplasia

Uncontrolled cell proliferation leading to a mass or Uncontrolled cell proliferation leading to a mass or tumor (neoplasm)tumor (neoplasm)

Occurs due to imbalance between cellular proliferation Occurs due to imbalance between cellular proliferation and cellular deathand cellular death

Normal growthNormal growth NeoplasmNeoplasm

Mutations in genesMutations in genescontrollingcontrolling-prolif or cell cycle.-prolif or cell cycle.-cytoskeletal -cytoskeletal inv’ed with contactinv’ed with contact inhibitioninhibition-programmed cell -programmed cell deathdeath-detecting and -detecting and repairing DNA repairing DNA damagedamage

What is cancer?What is cancer?

In addition, the neoplasm must also In addition, the neoplasm must also be malignantbe malignant

NOTE: Tumors that do not invade or spread are not cancerous, but NOTE: Tumors that do not invade or spread are not cancerous, but

referred to as referred to as benignbenign

growth no longer growth no longer

controlled and can now controlled and can now

invade neighboring invade neighboring

tissues and/or spread to tissues and/or spread to

more distant sites more distant sites

(metastasis)(metastasis)

Major types of cancerMajor types of cancerCarcinoma Carcinoma

Derived from epithelial cells, which line surface of skin and Derived from epithelial cells, which line surface of skin and organs, digestive tract, airways and mammary ductsorgans, digestive tract, airways and mammary ducts

Most common cancer type (89-90% of all reported cases)Most common cancer type (89-90% of all reported cases)

SarcomaSarcoma Derived from mesenchymal tissue – muscle, bone, cartilage, fat, Derived from mesenchymal tissue – muscle, bone, cartilage, fat,

connective tissuesconnective tissues

HematopoieticHematopoietic Leukemia – derived from white blood cells or their precursorsLeukemia – derived from white blood cells or their precursors

Lymphoma – involves cells of the lymphatic systemLymphoma – involves cells of the lymphatic system

Myelomas – involves white blood cells responsible for the Myelomas – involves white blood cells responsible for the production of antibodies (B lymphocytes or B-cells) production of antibodies (B lymphocytes or B-cells)

Cancer prefixesCancer prefixes

Examples: Examples: Osteosarcoma – cancer Osteosarcoma – cancer arising in bonearising in bone

Hepatocarcinoma – Hepatocarcinoma – cancer arising in the livercancer arising in the liver

Stages of tumor progressionStages of tumor progressionmore growth – abnormal more growth – abnormal cellular appearance; may cellular appearance; may become disorganizedbecome disorganized

uncontrolled cell division leading to an excess of cells

cells become primitive in cells become primitive in capability – invasive capability – invasive

potential existspotential exists

ability to invade ability to invade &/or metastasize&/or metastasize

Characteristics of cancer cellsCharacteristics of cancer cellsCytoskeletal changesCytoskeletal changes

Cell adhesion altered – cells able to moveCell adhesion altered – cells able to move

Changes in structure of nucleusChanges in structure of nucleus

Secretion of enzymes that enable them to invade Secretion of enzymes that enable them to invade

neighboring tissuesneighboring tissues

Unlimited number of cell divisionsUnlimited number of cell divisions

Growth in the absence of “go” signalsGrowth in the absence of “go” signals

Avoidance of cell deathAvoidance of cell death

Tumors stimulate the growth of blood vessels Tumors stimulate the growth of blood vessels

(angiogenesis)(angiogenesis)

Cancer in familiesCancer in families

Many forms have higher incidence in Many forms have higher incidence in

relatives than in general populationrelatives than in general population

Nearly 50 mendelian disorders where risk of Nearly 50 mendelian disorders where risk of

cancer is very high among relativescancer is very high among relatives

For other cancers, the increased incidence is For other cancers, the increased incidence is

2-3 fold higher for 12-3 fold higher for 1oo relatives – complex relatives – complex

disorderdisorder

Cancer as a genetic diseaseCancer as a genetic disease whether sporadic or familial, cancer is whether sporadic or familial, cancer is

fundamentally due to mutation in various genes fundamentally due to mutation in various genes controlling cell growth or cell deathcontrolling cell growth or cell death

once initiated, the cancer evolves by once initiated, the cancer evolves by accumulating additional mutations in other genesaccumulating additional mutations in other genes

leads to an ever-worsening cascade of mutationsleads to an ever-worsening cascade of mutations

Original clone of neoplastic cells can evolve into Original clone of neoplastic cells can evolve into numerous sublineages with different but numerous sublineages with different but overlapping mutationsoverlapping mutations

Tumor suppressor geneTumor suppressor gene Protooncogene Protooncogene

Classifying the genes involved Classifying the genes involved in cancerin cancer

OncogenesOncogenes – – mutant forms of genes mutant forms of genes

(proto-oncogenes) that positively regulate cell (proto-oncogenes) that positively regulate cell

proliferation and cell survival proliferation and cell survival -usu dominant, gain--usu dominant, gain-

of-fn mutationsof-fn mutations

Tumor suppressorsTumor suppressors – genes which function to – genes which function to

block tumor development by negatively block tumor development by negatively

regulating cellular growth-regulating cellular growth-usu need loss of both usu need loss of both

copiescopies

Cellular maintenance genesCellular maintenance genes – responsible for the – responsible for the

detection and repair of genetic damage in cellsdetection and repair of genetic damage in cells

OncogenesOncogenes

in altered (mutated) form, gene expression in altered (mutated) form, gene expression leads to abnormal stimulation of cell division leads to abnormal stimulation of cell division and proliferationand proliferation

have a dominant effect at the cellular level – a have a dominant effect at the cellular level – a single mutant allele is enough to change single mutant allele is enough to change cellular phenotype from normal to malignant cellular phenotype from normal to malignant (gain of function)(gain of function)

Mutations: gene, regulatory region, copy #Mutations: gene, regulatory region, copy #

normalnormal mutantmutant

OncogenesOncogenesin its normal form, in its normal form, the gene is called a the gene is called a proto-oncogeneproto-oncogene

Most proto-oncogenes Most proto-oncogenes are components of are components of signal transduction signal transduction pathways: pathways: translate extracellular translate extracellular signals into changes signals into changes in gene expressionin gene expression

Increase blood supply Increase blood supply to the tumor or inhibit to the tumor or inhibit apoptosisapoptosis

RET, METRET, METReceptor tyrosine kinasesReceptor tyrosine kinases-transduce an extracellular-transduce an extracellular signal inwardsignal inward-bind a ligand, conformational -bind a ligand, conformational change that results in kinase change that results in kinase activity, leading to phosphor-activity, leading to phosphor-lation of cellular proteinslation of cellular proteins-pt mut’s cause receptors to-pt mut’s cause receptors tobe constitutively activebe constitutively activeRET mut-multiple endocrine RET mut-multiple endocrine neoplasianeoplasiaMET mut-hereditary papillary MET mut-hereditary papillary renal carcinomarenal carcinoma

Ras, AblRas, Abl

MycMyc

RAS family of proto-oncogenesRAS family of proto-oncogenesOne of the first activated oncogenes discovered One of the first activated oncogenes discovered by the DNA transformation assayby the DNA transformation assay

Encodes a small guanosine triphosphate (GTP) –Encodes a small guanosine triphosphate (GTP) –binding protein (G-protein)binding protein (G-protein)

3 members of this family; H-RAS, K-RAS, N-RAS3 members of this family; H-RAS, K-RAS, N-RAS

Serves as an “on/off” switch to activate or Serves as an “on/off” switch to activate or inhibit downstream molecules when bound to inhibit downstream molecules when bound to GTPGTP

The protein’s effect is ended by self-directed The protein’s effect is ended by self-directed cleavage of GTPcleavage of GTP

RAS family of proto-oncogenesRAS family of proto-oncogenes

Ras associates with the plasma membraneRas associates with the plasma membrane

Ras relays signals from the cell surface Ras relays signals from the cell surface receptors to the nucleus, functioning as a receptors to the nucleus, functioning as a switchswitch

‘‘Active’ when GTP is boundActive’ when GTP is bound

‘‘Inactive when the hydrolyzed GDP is boundInactive when the hydrolyzed GDP is bound

RAS mutation in human RAS mutation in human cancerscancers

H-RAS mutated in 10% of all bladder cancer

K-RAS mutations in about 50% of colorectal cancers, 70-90% of pancreatic cancers and 30% of lung adenocarcinomas as well as in ovarian, breast skin liver and

kidney

N-RAS mutations have been detected in 20-30% of acute nonlymphocytic leukemias

RAS oncogene activation by RAS oncogene activation by nucleotide substitutionnucleotide substitution

Conversion to oncogene usually due to a point Conversion to oncogene usually due to a point mutation in the gene where:mutation in the gene where:

the ras protein is able to signal continuously, even the ras protein is able to signal continuously, even in in absenceabsence of GTP of GTP

the ras protein is the ras protein is unable to hydrolyze GTPunable to hydrolyze GTP to turn “off” the signalto turn “off” the signal

Leads to the continuous activation of multiple Leads to the continuous activation of multiple downstream signaling pathways inducing cell downstream signaling pathways inducing cell proliferationproliferation

Mutations in the 3 RAS genes are found in 10-Mutations in the 3 RAS genes are found in 10-15% of all human cancers 15% of all human cancers

Oncogenes are also activated Oncogenes are also activated by chromosome translocationsby chromosome translocations

Breakpoint can occur within Breakpoint can occur within introns of two genes: introns of two genes: chimeric protein with novel chimeric protein with novel properties – properties – Chronic Chronic Myelogenous Leukemia-Myelogenous Leukemia-Uncontrolled proliferation of Uncontrolled proliferation of white blood cellswhite blood cells

Arises in a bone marrow Arises in a bone marrow stem cell that is a precursor stem cell that is a precursor

to the granulocytes and to the granulocytes and megakaryocytesmegakaryocytes

These cells contain a chr These cells contain a chr 9;22 translocation – 9;22 translocation –

“Philadelphia Chromosome”“Philadelphia Chromosome”

Protooncogene ABL, a tyrosine kinase, is moved from its normal position on 9 to 22.Result: increased activity

Chronic Myelogenous Chronic Myelogenous Leukemia (CML)Leukemia (CML) Proto-oncogene ABL Proto-oncogene ABL

(tyrosine kinase) moves (tyrosine kinase) moves from 9q to the from 9q to the “breakpoint cluster region “breakpoint cluster region (BCR) on 22q(BCR) on 22q

Chimeric protein has Chimeric protein has increased tyrosine kinase increased tyrosine kinase activity but altered activity but altered structure and functionstructure and function

Requires secondary Requires secondary mutation to move into mutation to move into crisis phasecrisis phase

Effective drug therapy Effective drug therapy developed to target novel developed to target novel proteinprotein

Oncogenes are also activated Oncogenes are also activated by chromosome translocationsby chromosome translocations

Breakpoint can occur within Breakpoint can occur within introns of two genes: introns of two genes: chimeric protein with novel chimeric protein with novel properties – properties – Chronic Chronic Myelogenous LeukemiaMyelogenous Leukemia

Alternately, translocation Alternately, translocation may place proto-oncogene may place proto-oncogene downstream of a strong downstream of a strong constitutive promoter from constitutive promoter from another gene – proto-another gene – proto-oncogene is now expressed oncogene is now expressed at inappropriate time/place at inappropriate time/place – – Burkitt LymphomaBurkitt Lymphoma

Burkitt LymphomaBurkitt LymphomaB-cell tumorB-cell tumor

MYC proto-oncogene MYC proto-oncogene (transcription factor) (transcription factor) translocated from 8q24 translocated from 8q24 to 14q32, distal of the to 14q32, distal of the Ig heavy chain locusIg heavy chain locus

Ig enhancers or Ig enhancers or activating sequences activating sequences act on MYC – allowing act on MYC – allowing for unregulated for unregulated expression and expression and uncontrolled cell growthuncontrolled cell growth

http://tooldoc.wncc.edu/Infections/lymphoma.JPG• Solid tumor of B-lymphocytes

• Predominantly affecting young children

in Africa,

• one of the fastest growing malignancies

in humans.

• manifested most often as a large jaw

lesion expands rapidly over a period of

a few weeks to invade the orbit.

• Visceral involvement, usually an

abdominal mass

• Treatment of the jaw and eye areas is by

radiotherapy,while visceral involvement

requires systemic chemotherapy.

In all cases, translocation of MYC is the cause