1.     
INTRODUCTION:

1.1.  
Tumor 

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Neoplasm
is aberrant cell growth which forms a mass. It may be solid or fluid filled.
Neoplasm is also called as tumor. Every tumor need not to be carcinogenic. The
tumors can be differentiated in to three main types John Hopkins Medicine
Pathology, 29/11/2017

1
Benign tumors

2
Pre malignant tumors

3
Malignant tumors

1
Benign tumors: it is mass of tissue which forms tumor in different organs, skin
etc. the benign tumors are non-cancerous tumors. They are localized, and do not
spread in body. It can be treated, if it is left untreated it may be a reason
for some disease, because of its size.

They
are further divided into 6 types;

a)      Adenomas:
Benign tumor formed in epithelial tissue of gland or gland like structure.
Usually it does not require any treatment, if it is formed in sensitive organs
like colon it may turn into cancerous.

b)      Fibroids
: The tumor formed from connective tissue, even though they are not dangerous
but sometimes cause pain and bleeding.

c)      Hemangiomas:
It is a mass of blood cells, often formed from birth as birthmark. It generally
appears in red or blue color.

d)     Lipomas:
Lipomas are benign tumors formed of fat cells. They are soft movable, found in
back neck, arm pit, shoulder etc.

e)      Myomas:
Myomas are formed in wall of blood vessel or in muscle tissues.even there is a
possibility that myomas are formed in smooth muscle.

f)       Nevi/
moles: Very common tumor found on the skin of individual. It is localized and
do not spread from one part to another part.Sharma et al.,2009 John Hopkins Medicine Pathology 29/11/17, WebMD
29/11/2017

2
Premalignant tumors: the tumors are not yet turned into cancerous, but if it is
left untreated it will turn into cancerous. There are four types of
premalignant tumors.Sharma et al., 2009

a)      Actinic
keratosis: As the name indicates keratosis, it is related to skin. The skin
becomes patchy, crusty, scaly which is due to continuous exposure to sun.

b)      Dysplasia
of cervix: the normal lining of uterus wall is rehabilitated.

c)      Metaplasia
of lungs: the abnormal growth occurs in air sac, a tube which carries air.
Metaplasia is mainly caused due to prolonged smoking.

d)     Leukoplakia:
the thick patch forms in oral cavity which cannot be scratched easily. It is
commonly found in individual consuming tobacco products.

3
Malignant tumors: the malignant tumors nothing but cancer. The malignant tumors
divides rapidly, having double or triple the rate of normal cells.Sharma et al.,2009

Cancer

The
word “Cancer” covers more than 100 diseases which cover overall body, this make
it a major cause of concern WebMD 13/11/2017. Cancer it is one of the major
disease which starts with abnormal cell growth or improper growth of cell,
group of cell or tissue. There are mainly four types, based on the tissue type;
carcinoma, sarcoma, lymphoma and leukemia.. The lymphoma and leukemia are
related to lymphocytes and blood respectively. In cases of leukemia solid
tumors are not found. Sarcoma is related to mesenchyme tissue.
Carcinoma is related to epithelial tissue, which is very commonly found WebMD
13/11/2017. There are about 12 common types of carcinoma such as breast
cancer, colorectal cancer, bladder cancer, kidney cancer, lung cancer, and
lymphoma. Among them breast cancer is one of the major concern.

1.2.  
Breast
cancer

Breast
cancer (BC) mainly associated with malignant tumor found in breast vicinity of an
individual (Fig. 1). The breast cancer mainly found in females than in males. Considering
the types of breast cancer, invasive ductal carcinoma (IDC) is most common type.
Around 80% of breast cancers are IDC, 10% of cases are of invasive lobular
breast cancer, and remaining 10% account for rest other types like male breast
cancer, molecular subtypes of breast cancer, paget’s disease of the mammary
papillas, phyllodes tumors of the breast, recurrent & metastatic breast
cancer Breastcancer.org 9/12/2017 (Fig. 2).

Fig.
1: Schematic representation of the breast

Fig.
2: classification of breast cancer

Self-examination
of breast cancer can be performed with respect to the size, shape of breast,
texture of breast and mammary papillas, discharge from Mammary papillas, frequent pain in breast, armpit WebMD
4/12/2017. Clinically breast cancer is examined by screening tests, diagnostic
tests, monitoring tests Breastcancer.org  

1.3.  
Statistic

According
to GLOBOCAN survey, globally 14.1 million new cases of different cancer were
reported for 2012, with 8.2 of mortality attributed to cancer for the same
year. Total breast cancer cases in world are 1.67 million which stands second
highest among all the types of cancer. When prediction is done for 2020 the
number increases 1,671,149 to 1,979,022 which is about 18.42% increase, even
mortality rate increases to 19.30%(in 2012- 521,907 and in 2020- 622,676,
increased to 100,769). In India the new cases reported in 2012 is 144,937and it
may increase to 174,706 which is 20.53% increase with mortality rate increased
to 19.30%. GLOBOCAN2012, 31/11/2017

                   
Fig. 4 world map showing intensity of breast cancer

When
top 10 countries are considered with respect to the breast cancer ASR, Belgium
stands first for incidence and Bahamas stands first of mortality. There are top
3 countries with respect to the mortality rates. Those are Bahamas (26.3), New
Caledonia (23.4) and Barbados (22.1). Even though all these three countries do not come under top
3 incidences, there the mortality is high.

                                                             
Fig. 5 top 10 countries with
respect to breast cancer (ASR)                             

When
reported case are studied united states of America stands first for incident
cases followed by China and India. Even though India stands in third position
for incidence, it has most reported mortality cases.

                 Fig.
6 top 10 countries reported for incidence and mortality

Peculiarly when Indian population is
studied, there is two major cancers which effects mostly to female, breast
cancer and cervix uteri. Breast cancer is found in more number with maximum
mortality cases in India which become major concern for future.

Fig.7 chart showing reported cases
for mortality and incidence for various cancers in India

1.4.  
Risk
factors

There
are several factors effecting breast cancer. Such as the age, reproductive
history (age at menarche and menopause, age at first pregnancy), previous
benign disease, lifestyle, alcohol consumption, exposer to ionic radiation, hormone
therapy and family histories. When family history is concerned it directs to genetically
linkage McPherson et al.,2000.

1.      Age:
Out of 8 cases one case of invasive breast cancer is found in younger age
than of 45yrs.by then two out of three IDC cases are found in women of 55 or
more age. When the status of estrogen receptor in breast cancer is
deliberated,  ER positive BC risk goes on
increasing with age, but ER negative BC risk increases till 50 years and then
becomes constant. So the risk factor with respect to age is higher in range of
44?55years.Breastcancer.org
9/12/2017, Ban and Godellas 2014

 

                   Fig.8 the graph showing risk increases with age 15

2.      Gender: Being
a female is a major risk. The complete growth of breast in female is continued
till 14 years with development of glands, but in male the growth contain only
fat. When compare to breast growth in male and female, female having more
estrogen and active cells. There is only 1% chance of getting breast cancer in
male. Breastcancer.org 25/10/17

3.      Ethnicity:
the breast cancer more likely to see in white’s than African American,
Hispanics and Asian women. But African American women’s are more likely to
develop with intensive and advanced breast cancer which even results in death.
Even though the incident rate is more in white’s but result may be due to lack
of availability of mammography and proper treatment for it, life style such as
diet, weight, smoking, alcoholism etc.Breastcancer.org 25/10/17, Ban and
Godellas 2014

          Fig.9 Graph showing risk with respect
to ethinicity

4.      Geographical
Location:  The change between East Asia
and Western countries is fading but is still about five times more. Survey of
emigrants from Japan to Hawaii show that the rates of breast cancer in
emigrants assume the rate in the host country within one or two age groups,
indicating that environmental factors are of greater impact than genetic
factors.

5.      Reproductive
and Hormonal factors

a.       Age:
the age and menopause are interred related to each other. Premenopausal the
risk of incident is 10% more than post. Post menopause the incident rate
decreases radically. Mostly the breast cancer incident cases are found in
younger age.

b.      Menarche
and Menopause: female
who start menstruating in younger age or who have stopped there menstruation
has a greater risk of developing breast cancer. Natural menopauses after the
age of 55 are double as likely to develop breast cancer as women who achieve
the menopause before the age of 45. Female who undertaken bilateral
oophorectomy before the age of 35 have only 40% of the risk of breast cancer of
women who have a natural menopause.

c.       Pregnancy:
Nulliparity and delayed pregnancy both increase the lifetime incidence of
breast cancer. The risks of breast cancer in women having pregnancy after the
age of 30 is about double that of women who have their first child before the
age of 20. The highest risk groups are those who have a first child after the
age of 35. These women appear to be at even higher risk than nulliparous women.
Second pregnancy at the younger age reduces the risk of breast cancer.

d.      Oral
contraceptive: if female after taking prolonged contraceptive pills, and sudden
if she stop taking them, there is a possibility that she may incident with
breast cancer. The younger age appear to have a higher relative risk than women
who begin oral contraceptive use at an older age. This higher relative risk
applies at an age when the incidence of breast cancer is however very low.

e.       Hormone
replacement therapy: people under HRT and those who have stopped use 1­4 years
previously the relative risk of having breast cancer diagnosed increases day by
day. The risk of breast cancer appears higher with combined estrogen and
progestogen combinations. But does not lead to mortality McPherson et al., 2000.

6.      Weight:
Obesity is associated with a twofold increase in the risk of breast cancer in woman
whose menstruation is stopped whereas among premenopausal women it is
associated with an abridged incidence.

7.      Alcohol
consumption:  usually alcohol does not
show that much risk than that of dietary products

8.      Smoking:
Smoking is of no importance in the etiology of breast cancer.

9.      Diet:
it usually related to the total intake of unwanted fat and incident of breast
cancer, even though the risk factor may not be so strong.

10.  Family
background: around 10% of breast cancer cases is due to transfer of gene reason
for breast cancer from ages. The gene may be present in any of family member
even though it is not expressed in them but it can be passed to offspring.
McPherson et al.,2000.

Human genome is made of DNA which contains genes
which are related to the respective function in the body Dawson et al.,2010. These genes usually
present in the chromosome, the coiling of chromosomes are mechanized in the
manner where it is silenced in order to suppress its expression .but in case of
cancers the genes are failed to silence, and shows its expression in tumor
formation. The study relay on the genes, its changes and modification which is heritable
called as epigenetics Deans et al.,.

1.5.  
Epigenetics
and cancer:

The term ‘epigenetics’ is coined by Conard
Waddington in 1942 Deans et al.,2008,
according to his statement “epigenetic is heritable changes in a cellular
phenotype that were independent of alterations in the DNA sequences” Dawson et al.,2010. The present statement states
‘the study of heritable changes in gene expression that occur independent of
changes in the primary DNA sequence’ MEDICAL NEWS TODAY 29/11/2017. Epigenetic
changes relate with alteration in molecular phenotypes by various changes
involving histone modification, gene silencing, DNA methylation, protein
modification, noncoding RNA modification. The chemical alterations take place
usually at CpG islands. Epigenetic modification results in activation or inactivation
of protein moieties Jovanovica et al.,2010
the epigenetic mechanism mainly resides on two main events, DNA methylation and
covalent modification of histone.

DNA
methylation:  most of epigenetic
modification is formed of DNA methylation. Where the genes are metylated in
order to silence of it. The methyaltion is induced by DNA methyltransferease
enzyme(DNMTS). It may have different grades of methylation such as mono,di,
trimethylation. In normal cells methylation takes place in order to retain
proper function of cell but in cancerous cells it will be mismethylated result
in cancer formationEsteller 2008, Sharma et
al.,2009

Covalent modification of histone: histone protein
which plays major role in chromosome coiling contains globular C- terminal and
N-terminal tail.  Usually N-terminal end
undergoes modification such as acetylation, ubiquitylation and phosphorylation
on particular residues result is changes with transcription, translation and
other cellular activity. Improper modification result in inhibition of tumor
suppressor gene which induces the growth of malignant tumors. Sharma et al.,2009

Fig.10 Epigenetic alterations in the genesis of cancer

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