Cancer inheritance #cancer #inheritence #health

 CANCER GENETICS

Subrata Sinha

From the time Boveri observed that chromosomal changes are

a feature of cancer, it has been thought to be a disease caused

primarily by alterations in the genome of the affected cells. Today,

the notion of cancer being a consequence of genetic alterations, is

almost intuitive and the advances in molecular biology and genomics

have given us many tools to understand and possibly to combat

cancer. Since science has always existed in a continuum, the genetic

alterations in cancer have to be understood in the context of cellular

organization , differentiation , tissue organization host response and

susceptibility angiogenesis etc.

The properties that are taken to typify cancer cells are also

present in normal cells. These include cell division, migration and even

invasion (as exemplified by the trophoblast cells). However what marks

out cancer cells is dysregulation and inappropriate expression of these

attributes. Typically the genetic alterations in cancer can be said to

include three major types of genes, oncogenes, tumour suppressor

genes and genes that preserve the integrity of the genome. It must

be kept in mind that cancer is a multi-step process and several genetic

alterations are required for a full blown cancer phenotype.

Oncogenes

These are today known to be cellular genes that when mutated and/

or inappropriately expressed in a manner that increases their activity

result in a malignant phenotype. Classical examples include src, ras

and myc oncogenes. These genes are very much the key components

of cellular regulatory processes eg. the src gene is codes for a

tyrosine kinase, the ras gene for a G protein and the myc gene for a

nuclear protein that is involved in DNA replication.

Oncogenes were first discovered in acutely transforming

retroviruses (Rous Sarcoma Virus). When these viruses infect

immortalized but untransformed cells in culture they generate a

neoplastic phenotype. It was subsequently found that these viral

oncogenes were not naturally occurring viral genes but picked up

from the cellular genome and subsequently mutated or over expressed

to generate cellular transformation. A single mutated oncogene cannot

transform primary cells and the requirement for oncogene co-

operativity is in concordance with the multi-step theory of

carcinogenesis derived from classical studies. Oncogene co-operavity

usually requires cooperation between oncogenes belonging to different

groupings eg. nuclear (eg myc with cytoplasmic eg ras).

Tumour Suppresor Genes (TSG)

These genes can be compared to the brakes of a car, and function

in the cell to regulate cell division. Loss of genetic matter is also a

key event in the generation of neoplasia, and the same can be

demonstrated by cytogenetic techniques. Molecular tools have been

able to further define the loss of genetic matter. Typically there is

loss of one allele of a TSG while the other is inactivated by point

mutation. The concepts of TSGs were demonstrated first with the

Retinoblastoma gene (RB). Commonly affected TSGs include the p53

gene (affected in almost half the human malignancies) the Wilms

tumour gene the p16gene etc.

Genes controlling genomic integrity

These have also been called caretaker genes. Inactivation of such

genes leads to genomic instability and thus markedly increases the

probability of alterations in the oncogenes and the TSGs. DNA

mismatch repair genes have been extensively studied and include

the hMSH2 and hMLH1 genes which are commonly affected in human

malignancies. Again as the case of most oncogenes and TSGs,

homologues of such genes can be traced back to the yeasts indicating

the fundamental similarity of these biological processes. DNA

mismatch repair defects manifest as unusually rapid expansion and

contraction of microsatellite repeat sequences. Inherited defects in

such genes are exemplified in Hereditary Non Polyposis Colon Cancer

(HNPCC), where analysis of microsatellite repeats in leucocyte DNA

forms a basis of diagnosing the affected siblings in a family. The

affected individuals are subjected to regular investigations including

colonoscopy. Increased genomic instability also includes several other

aspects, the implications of which are under study. These include

aneuploidy including genetic loss and translocations, increased

which are shown to have a mutation in codon 249. However this is

not always true. This observation could be a manifestation of different

levels of aflatoxin exposure and or of other modifying factors like DNA

repair.

The Human Genome Project(HGP) and Microarray Technology in Cancer

No discussion of modern cancer genetics is complete without a

mention of the Human Genome Project and the role of microarray

technology in the study of cancer genetics. While a detailed discussion

of the Human genome Project is beyond the scope of this report, a

detailed and precise knowledge of each individual gene and its

regulatory elements has contributed (along with other knowledge) to

the identification of a number of possible anti-cancer targets. This major

quantitative and qualitative leap in our knowledge and understanding

of tumours promises to change our way of thinking about cancer.

The sheer power of microarray technology where one can study tens

to hundreds of thousands genetic segments in one experiment gives

a picture of the global nature of alterations in the cancer genome and

gene expression, where earlier we had to be content with studying a

much smaller number of events. It is also expected that the

technological advances brought about by the HGP will translate

themselves into techniques that give the clinical laboratory much more

investigative power than it previously had.

Points of intervention

Genetic aspects of cancer potentially lend themselves to intervention

in a variety of ways. These include predictive, diagnostic, prognostic

and therapeutic aspects. However it is also a fact that right now

most of the cancer interventions do not rely on the knowledge derived

from genetic studies on cancer. Neverhteless, there are strong

indications that this outlook is likely to change in the near future.

Drugs exploiting selective genetic and functional differences in cancer cells

Cancer therapy today is mostly based on anti-mitotics and this lack

of selectivity results in increased toxicity. However increasing

knowledge of definite genetic alterations in different classes of tumours

can help in the design of drugs that will selectively attack tumour

cells. The drug gleevec has provided proof of the principle that specific

tyrosine kinase inhibitors can be used for cancer therapy, mainly

related to CML, but also valid for some other cancers as well. Similarly

Epidermal Growth Factor Receptor based protein kinase has also been

targeted by small molecular weight inhibitors with promising results.

Another class of drugs are inhibitors of the farnesyl pathway. These

target mutant ras proteins as ras is anchored o the plasma membrane

by a farnesyl tail.

Gleevec has been shown to be clinically effective. Looking at

the number of drugs in trials at various stages and the explosion in

knowledge based drug design, the number of such molecules is bound

to increase. Another example that has been around for some time is

tamoxifen. If one goes by definition of oncogenes Estrogen Receptor

also functions as one in the context of breast cancer, and tamoxifen

is a specific anti cancer compound.

Small molecules no doubt have an advantage when it comes to

therapy, however derivatised oligonucleotides have been shown to

have useful properties in terms of specificity, stability and bio-

availability and many eg anti c-myc oligos are in clinical trials, often

in conjunction with conventional chemotherapy. Inhibitor RNA

technology and ribozymes may be technologies of the future.

The examples so far are about inhibiting the actions of mutant or

hyperactive oncogenes. What about restoring the functions of tumour

suppressor genes? Gene therapy has been tried for restoring p53

function in a variety of tumours and shown to be effective in animal

experiments and clinical trials. However the results of restoring p53

are expected to vary from tumour to tumour. Small molecules have

also been designed to restore the function of mutant p53 and they

hold out al lot of promise.

Antibody Based therapy in Cancer

Recombinant antibodies, including chimaeric and humanized antibodies

have revolutionized antibody based therapy, and currently form the

class of recombinant proteins in various stages of approval.

Recombinant antibodies approved by the FDA include Rituximab (for

Non-Hodgkin Lyphoma), Trastuzumab (Breast cancer) and

Gemtuzumab (Acute myeloid leukaemia). Such antibodies target cell

surface antigens on the surface of malignant cells, and apart from

their direct effects have been shown to sensitize the tumour to other

therapeutic modalities.

Diagnostic and Prognostic Markers

The immediate applicability of genetic studies to diagnostic and

prognostic applications is growing. As genes ultimately have to function

through the increased expression of proteins, IHC can play a role in

addition to direct detection of genetic alterations. In breast cancer

HER IHC already has place in the management of estrogen receptor

(ER) negative cancer and herceptin has emerged as an emerging

therapy for such tumours. Using classical therapeutic modalities HER

over expression is a negative prognostic factor in breast cancer.

Another oncogene that have been used for prognosis is Nmyc and

its amplification is associated with poor prognosis in neuroblastoma.

There have been a lot of studies on the mutational status of p53 in a

variety of cancers but it is yet to become an accepted part of

therapeutic strategies.

Loss of hetrozygosity (LOH) of 1p, 19q in oligoastrocytomas has

turned out to be a valuable genetic marker of response to

chemotherapy using procarbazine, carbamazipene and vincristine

(PCV). Since chemotherapy is costly and toxic and the genetic

markers are clearly able to distinguish responder from non responder

genetic typing will soon become an accepted part of management of

such tumours.

Genetic markers from serum DNA: Tumours shed a considerable

amount of DNA into the serum, which could be utilized for determining

the presence or recurrence of the tumour and also give an indication

of tumour load. This is technically difficult because of the presence

of a normal background. How ever some determinations like serum

mutant p53 levels have lot of potential.

Molecular typing of hematological malignancies has an important

role because differences in behavior of different sub sets of leukemias

and lymphomas. Molecular probes include studies of T cell receptor

re arrangement, BCR-ABL fusions etc. These can be used for studies

of tying, response to chemotherapy, follow up and the detection of

minimum residual disease.

While molecular markers have an important role in tumour staging,

with increasing knowledge of markers that may affect the transition

from pre-neoplasia to neoplasia may help identify potentially threateninglesions at sites accessible for biopsy or FNAC. These include tumours

of the skin, breast, cervix, lymph nodes, liver etc.

Genetic Susceptibility to Cancer

While familial cancers do form a high percentage of the total cancer

burden, they .remain a source of misery to the affected families.

However the identification of specific germ-line mutations provides an

opportunity to identify susceptible individuals and prevent or markedly

improve the outcome by timely interventions. Similarly, those

individuals in the affected families who do not carry the mutations

can be spared the mental agony of uncertainty and the physical agony

and costs of repeated screening. This screening for mutations in

Brcal I And Brca II genes in breast cancer families is an established

management strategy in the West. However before it is brought to

Indian situation the frequency of such mutations in familial breast

cancer in India remains to be determined. Li-Fraumeni's syndrome is

rare and characterized by the inheritance of a mutated p53 gene.

While these markers are not the stage to be incorporate into public

health programs it is expected that with continuing research more

genetic indicators for familial cancers will be discovered. Microsatellite

instability is an indicator of HNPCC as discussed earlier. This is

offered as an investigation to the affected families in advanced centers

in the West.

The human genome project has brought an unprecedented amount

of information, but most of the data is of general nature and not

suitable for direct extrapolation to the diverse ethnic groups that

constitute the Indian population. The Department of Biotechnology has

initiated a ' People of India ' project to characterize the genetic make

up of these groups with reference to their ethnicity. It is expected

that this research will lead to the identification of suitable genetic

markers (eg. single nucleotide polymorphisms and microsatellites)

that indicate cancer susceptibilities of different populations.

Genetics and toxicity

Genetics also has something to offer to individuals receiving

conventional chemotherapy. There is a considerable amount of

literature linking various genetic polymorphisms to drug metabolism

and toxicity. It is expected that such genetic signatures will constitute

a major expect of planning drug regimens in neoplasia. This also

has the potential of reducing cost of management by tailoring

chemotherapy to those patients who benefit the most.

Policy Aspects Related to Genetics

As most of the information and interventions related to the genetics

of cancer cells is new and still evolving, it is difficult to assess the

feasibility of each individual component, However it is clear that the

impact of new information and technology will be felt on various aspects

of cancer management.

There is no doubt that the cost of cancer chemotherapy is

prohibitive. The fact that the results are often equivocal often make

the costs unjustified. However, if because of the identification of

genetic targets in cancer cells , there is a increased efficacy and

reduced toxicity, resulting in increased cure rates or at least marked

increase of quality of life, policy decisions have to be taken to supply

these 'essential' drugs of the future at a reasonable cost. In an

increasingly older population, with a correspondingly higher

demographic predisposition to cancer this issue will increasingly

confront policy makers. The issues of intellectual property, and the

definition of what constitutes a life saving drug that needs to be made

available cheaply to the population will need to be addressed.

Generic Production of Recombinant Proteins:

a case for reducing costs

HBS Ag can be called a cancer vaccine, also many recombinant

proteins like interferons are important in cancer therapy. The

technology for producing such recombinant proteins is comparatively

simple. For the moment product patents are not involved, and anyway

for these and several other recombinant products, the patents are

expected to expire soon. One aspect of policy intervention could be

to reduce prices to better reflect the low costs of production of several

recombinant products like HBS Ag and interferons. This will have a

multiplier effect on healthcare.

Genetic predisposition to cancer:

occupational and environmental exposure

It is expected that it will be possible (though not perhaps to a large

extent in the near future), an increasing number of individuals and

groups with a significantly increased susceptibility to cancer. They

can be counseled about employment and other modes of risk

avoidance. However, like other similar offshoots of the Human Genome

Project an ethical frame work needs to be made where the right to

privacy, various aspects of discrimination at workplace, nature of

health insurance etc can be incorporated into fair and balanced

guidelines.

Genetic aspects of drug trials and the incidence of toxicity

The incidence of drug toxicity in an individual is often unpredictable

and because of the occurrence of major toxic side effects in even a

small percentage of individuals, many drugs are permitted for use. It

is expected that in the field of anti-cancer drugs, as for other classes

of drugs, genetic predictors of toxicity will be more precise. This will

reduce risks and individualize therapy to the ' most effective and least

toxic' combination for any individual. However this requires significantly

more research into the genetic backgrounds of individuals, the various

ethnic groups of India and clinical work ups of individual patients.