Medical Medical informaticsinformatics

In this presentation……

Part 1 – Foundations

Part 2 – Cancer

Part 3 – Detailed Look into Cancers

Part 4 – Response of Cancers to Chemotherapy

Part

1

FoundationFoundationss

Bioinformatics and disease link

• Gene expression data analysis could give important clues for reasons behind cause of various diseases, especially about the behaviour and growth of disease causing germs– Communicable diseases – malaria, typhoid,

cholera– HIV/AIDS– Cancer– Dengue

smaller sets are preferred for processing…

• Large samples of over 200 genes are not helpful since if all of them are correlated with a particular class, it is unlikely that they all represent different biological mechanisms and hence are unlikely to add information not already provided by others

• Though excellent research work has been carried out in last three decades, there are no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction)

Some noted works• Golub, Slonim et al (1999) published a paper on

molecular classification of cancer. This relates to their study of class discovery and class prediction by gene expression monitoring

• Slonim, Tamayo et al (2000) subsequently studied class prediction and discovery using gene expression data

• Ramaswamy et al (2001) brought out multiclass cancer diagnosis using tumor gene expression signature

The p53 protein

• One of the fly genes with a human counter part is p53, a so-called tumor suppressor gene that when mutated allows cells to become cancerous

• The p53 gene is part of a molecular pathway that causes cells that have suffered irreparable genetic damage to commit suicide

• It was identified that just as in human cells, fly cells in which the p53 protein is rendered inactive, lose the ability to self-destruct after they sustain genetic damage and instead grow uncontrollably

DNA repair

• Using yeast genome, scientists discovered the fundamental mechanism cells use to control how and when they divide

• This has enlightened everyone about cell division and DNA repair, processes that are important in cancer diagnosis and control

• One of the findings is that the common chemotherapeutic drug ‘cisplatin’ is particularly effective in killing cancer cells that have s specific defect in their ability to repair their DNA

Part

2

Third World Third World DiseasesDiseases

Canadian team sequencing SARS virus

• Scientists from the Genome Science Centre at the British Columbia Cancer Agency are sequencing the Severe Acute Respiratory Syndrome (SARS) virus

• 30 genome researchers from 11 countries are involved in the project

• Early identification using electron microscopy, PCR and viral microarray have identified the SARS virus as a corona virus

AIDS tests have a flaw?…

• The ELISA and Western Blot tests look for the antibodies to HIV in blood samples

• But these antibodies are also found in samples of patients whose immune systems have been activated by several other conditions – like tuberculosis, multiple sclerosis and even warts

• These two tests actually look for the p24 protein which is found in healthy persons also

The HP virus• After breast cancer, cervical cancer kills more

women each year than any other cancer• It is particularly so in developing countries, where

screening is not widespread• Lasting infection from certain strains of a common

sexually transmitted virus – human papilloma virus (HPV) – causes almost all cervical cancers

• HPV was first linked to cervical cancer in 1983• Infection most in women of age group 16-23 years

Scourge of the HP virus

USA Developing countries

World wide

New cases 13,000 376,000 470,000

Deaths 4,100 192,000 232,000

Proportion of cancers worldwide linked to papilloma virus infection

Types of cancer Figures in %

Cervical cancer 99

Anal cancer 85

Cancer of vulva, vagina and penis 50

Third world diseases

• Asthma• Cystic fibrosis• Huntington’s disease• Sickle cell anemia• Malaria• Tuberculosis• Typhoid• HIV/AIDS

• SARS

Main targets for drug design as per WHO report Jan 2002

• AIDS

• Tuberculosis

• Malaria

Life style drugs

• Toe nail fungus

• Obesity

• Baldness

• Face wrinkle

• Erectile dysfunction

• Separation anxiety of dogs, etc.

Part

3

CancerCancer

Cancer

• It has existed all along with man

• Twenty-five centuries ago, Hippocrates, called it karkinois because the swollen blood vessels going and coming from the tumor mass, gave the appearance of the claws of a crab

• Susruta described cancer as a tumor which would ulcerate and would not cure, and “sow its seeds in other parts of the body”

Cancer treatment

• Cancer being more common in older people, increasing life span of man is providing more and more candidates for getting the disease

• Surgery to treat it has been used since centuries ago

• Radiation was used to treat breast cancer within one year of Roentgen’s discovery

• World War II provided the first drug in the form of nitrogen mustard to kill cancer cells

Cancer cause

• Cancer arises from the abnormal and uncontrolled division of cells, known as cancer cells, that then invade and destroy the surrounding tissues

• Cancer cells, in other words, refuse to stop multiplying and continue to increase in number

• It is the failure to stop multiplying which is the hallmark of cancer

• This they do even at the cost of other normal cells of body which are starved to death for lack of nutrition

Physico-chemical causes of cancer

• Benza pyrene (found in coal, tar, etc.)• Asbestos causes mesothelioma, cancer of the pleura• Dyes, synthetic colors• Aromatic amines, polycyclic aromatic hydrocarbons• Urethane• Metals like nickel, chromium, arsenic, beryllium• Harmones• Aflatoxin, pesticides, insecticides• Diethy stilbesterol (medicinal compound/female sex

harmone)

Other causes of cancer

• Genetic and personal factors – age, sex, race, marital status, heredity, socio-economic status

• Immune deficiency

• Environmental

• Virus, e.g., polyoma virus causes leukemia

Cancer cells vs. normal cells• Cancer cells are different from normal cells in some

aspects• They do not remain confined to one part of the body• They penetrate and infiltrate into the adjoining tissues

and dislocate their function• Some of the cancer cells get detached from the main

mass or site of origin and travel by blood cell and lymph channels to sites distant from the original tumor and form fresh colonies, called metastasis or secondary growths, in other organs where they grow at the cost of the normal cells

• This is how they destroy the well-regulated functioning of the body and bring about its end

Fast and slow-growing cancers

• A cancer may be slow- or fast-growing• The rate of growth depends on the tissue in which it

occurs and also on the inherent character of the type of cancer

• Rapidly growing cancers are those which send metastasis in other organs, are much more dangerous

• Sometimes the primary cancer in the first stage of development grows slowly, as for example, that of the stomach and remains unnoticed, while the secondaries spread rapidly in the liver, abdominal lymph glands, etc. These secondary cancers are first noticed

Tumor• Growth of cancer cells leads generally to formation of

a nodule or tumor; hence cancer is also called a tumor• If it is superficial, it is firm to touch, gets fixed to

surrounding tissues and is not freely moveable• However, every nodule is not cancer• Some like warts, cysts, or adenomas are benign and

are easily treated• But in order to be sure whether a nodule is cancerous,

a bit of the nodule is taken and examined under the microscope, which generally gives a correct diagnosis

How does cancer spread?

• Cancer spread occurs through any or all of the three routes– Local spread: cancer infiltrates the adjoining

parts, organs, tissues, etc.– Lymphatic spread: the lymph glands or nodes

trap the cancer cells present in the lymph fluid and cancer grows within them. Progressive spread along lymph vessels and glands may occur and in the process quite distant glands may become involved

– Bloodstream spread: if cancer invades blood vessels then the cancer cells may break into the bloodstream and be carried to other parts of the body and settle over there, producing secondary cancers. The major site of spread in cases of bowel cancer is liver. The lungs are the commonest site of metastasis from other cancer sites. The spread to many other organs is also common

Is cancer inherited?

• There are cases of some families, several members of which have suffered from cancer

• Scientists have propagated some strains or breed of mice in which a large number of males developed lung cancer and over 90 percent of females breast cancer

• A careful analysis of data shows that certain types of cancer are hereditary and there is a likelihood of cancer of a particular tissue or organ developing in the descendants of persons who have suffered from cancer

Cancer cure is expanding…

• In the 1950s, only 30 percent cancers were curable

• By 1977, that percentage had risen to 41

• By 1980, 45 percent of all serious cancers were curable

• This percentage is increasing fast

Fighting cancer

• Fighting cancer is not just hoping to discover a “magic bullet” to annihilate it

• It is much broader a problem– Early detection– Curative measures– Rehabilitation of the patients– Psychological problems faced by the patient

and relatives

Support sciences

• Interpretation of tumor data would involve an experienced hematophothologist for tumor morphology, histochemistry and immunophenotyping analysis

• Histopathology is the science that studies pathologic tissues. Just as in the case of all other branches of biological sciences, bioinformatics is poised to bring monumental changes to this branch as well. It is expected that it would also greatly influence the cancer pathogenesis and pharmacology

Support sciences

• It was found that genes useful for cancer class prediction may also provide insights into cancer pathogenesis and pharmacology

• The National Cancer Institute in USA maintains a project called Human Tumor Gene Index. More than 50,000 genes active in one or more cancers have been identified; with over 6,000 genes active in breast cancer cells, 277 that are not active in other tissues

Signs and symptoms• Cancers of various types and at various sites

manifest themselves in a variety of ways• On external surface, any thickening of the

tissues, formation of nodule or tumor, persisting sores and ulcers, can be feature of cancer

• Internal cancers may grow for some time before they cause any symptom. But weight loss, anaemia and low-grade fever in older people even without any other symptom, should arouse suspicion

Any manifestation may be cancer…• A lump or hard area in the breast• A change in a wart or mole• A persistent change in digestive and bowel

habits, e.g. constipation• A persistent cough or hoarseness in a smoker• Bleeding of vagina at times other than the

menstrual• Non-injury bleeding from the surface of skin,

mouth of any other bodily orifice• Any ulcer that does not get well• Unexplained loss of weight• Unexplained diminished or lost appetite• Unexplained low-grade fever

Cancer in children

Type % of total cancersLeukemia 30

Nervous system (retinoblastoma) 12

Bone sarcoma 12

Soft tissue sarcoma 12

Neuroblastoma 10

Wilms’ (kidney) tumor 8

Lymphoma 8

Hodgkin’s disease 6

Others 2

Cancer on older people

• Cancer occurs more often in people after 50 or 60 years of age

• In still older people, i.e. 80 years or above, some characteristics of cancer have been noted during life and in post-mortem studies of people who have died of causes other than cancers

Cancer in older people

• Small microscopic cancers of the prostate were very common in males

• Lung and stomach cancer were seen in many cases both in males and females

• Lung cancer of the type of adenocarcinoma, was found often and was commoner in females than males

• Multiple cancers arising in different organs at the same time was not an uncommon feature

• Lesions regarded as precursors to cancers were often observed in stomach, colon and lungs

• The rate of growth of cancers in general was slow

Cancer situation in the World

• Cancer is the second common cause of death in the developed countries next to cardiovascular (heart and blood vessel) disease

• In Europe and North America, approx. 1-5 die of cancer

• According to WHO, out of an estimated total of 50 million are attributed cancer, and the number of deaths from cancer throughout the world is increasing

Cancer situation in India• Approx. 500,000 new cases of cancer occur every

year in India• As the human life span is increasing in India, more

cases of cancer are observed here also• Cancer is thus regarded as an emerging health

problem in India• According to Dr. D J Jussawalla, Indian Cancer

Society, “Cancer is one of the 10 leading causes of death today in India, and is advancing in rank year by year”

Indian scenario

• The figures given by Indian Cancer Society state that about 1.5 million people suffer from cancer at any given point of time in India

• Oral cancer and cervix cancer account for the major causes of cancer in this country

Part

4

Detailed Look Detailed Look into Cancersinto Cancers

Broad groups of cancers• Carcinoma – any cancer that arises in epithelium,

tissue that lines the skin and internal organs of the body• Sarcoma – any cancer of connective tissue. These

tumors may occur in any part of the body, as they arise in the tissues that make up an organ rather than being restricted to a particular organ. They can arise in fibrous tissue, muscle, fat, bone, cartilage, blood and lymphatic vessel, etc.

• Leukemia – it is a cancer of the blood in which the bone marrow and other blood forming organs over-produce immature or abnormal white cells

• Lymphoma – any malignant tumor of lymph nodes or lymph gland

Types of cancers known

• lung

• breast

• thyroid

• nerve system

• muscles

• genito-urinary system

• leukemia

• lymphoma

• skin

• brain

• bone

• gastrointestinal tract

Leukemias and lymphomas

• Leukemias– Acute leukemia– Chronic leukemia

• Lymphoma– Hodgkin’s lymphoma– Non-Hodgkin’s lymphoma

ALL/AML

• AML affects various white blood cells including granulocytes, monocytes and platelets

• Leukemic cells accumulate in the bone marrow, replace normal blood cells and spread to the liver, spleen, lymph nodes, central nervous system, kidneys and gonads

• ALL is a cancer of immature lymphocytes, called lymphoblasts (sometimes called as blast cells). Normally, white blood cells repair and reproduce themselves in an orderly and controlled manner but in leukemia the process gets out of control and the cells continue to divide, but do not mature

• ALL is further divided into two subcategories viz., T-lineage ALL and B-lineage ALL

Mix of cancers

• The cases become extremely complex when one type of cancer pretends to be another or when a mix of cancers accidentally is identified as cancer of only one type

• Some particular subtypes of acute leukemia have been found to be associated with specific chromosomal translocation

• The samples for testing cancer or leukemia comprises of bone marrow and peripheral blood samples and thereafter RNA prepared from bone marrow or blood cells would be hybridized

Cancer of the brain

• Glioma

• medullobastoma

Cancer of thyroid

Cancers of gastro-intestinal tract

• Cancer of the mouth

• Cancer of the oesophagus

• Cancer of the stomach

• Cancer of the colon and rectum

• Cancer of the liver

• Cancer of the gall-bladder

• Cancer of the pancreas

Cancer of the lung

Cancer of the breast

• The genes BRCA1 and BRCA2 are linked to breast and ovarian cancer, whereas the MLH1 gene on human chromosome 3 is associated with colon cancer and MMAC1 gene mutates to generate a protein responsible for brain and prostate cancer

Cancers of genito-urinary system• Cancer of the uterine cervix • Cancer of the uterus• Cancer of the ovary• Chloriocarcinoma• Cancer of the testes• Cancer of the prostate• Cancer of the penis• Cancer of the urinary bladder• Cancer of the kidney

– Hyperneproma– Wilm’s tumor

Neuroblastoma

Cancer of the muscles

• Also known as rhabdomyosarcoma

Cancer of the bone

• Osteogenic sarcoma

• Ewing’s sarcoma

• Multiple myeloma

Cancer of the skin

• Squamous cells cancer (rodent ulcer)

• Malignant melanoma

Part

5

Response of Response of Cancers to Cancers to

ChemotherapChemotherapyy

Leads to cure• Blood cancer or acute lymphoblastic leukemia in

children• Cancer of lymphatic system or Burkitt’s lymphoma• Hodgkin’s disease – a malignant tumor of

lymphatic system• Wilm’s tumor or tumor of kidney common in

children• Cancer of muscle or rhabdomyosarcoma• Cancer of testes or teratoma• Cancer of the placenta or choriocarcinoma• Cancer of bone common among children or

Ewing’s sarcoma

Leads to prolongation of life

• Cancer of breast

• Cancer of the ovaries

• Cancer of lung, small-cell anaplastic type

• Non-Hodgkin’s lymphoma

• Chronic lymphocytic leukemia

• Acute myeloid leukemia

• Brain cancer or medulloblastoma

Leads to marginal benefit

• Cancer of stomach

• Cancer of the pancreas

• Bone cancer or myeloma

• Soft tissue arcoma

• Cancer of urinary bladder

• Cancer of thyroid

Leads to no benefit

• Cancer of lung, squamous cell type

• Cancer of colon

• Cancer of the oesophagus

• Cancer of skin or melanoma