Potential gene network for the health effect of exposure to pcb fs on human diffuse large cell lymphoma

THAI NGUYEN UNIVERSITY
UNIVERSITY OF AGRICULTURE AND FORESTRY

NATIONAL TSING HUA UNIVERSITY

THAVISACK MIVONGSACK

TITLE: POTENTIAL GENE-NETWORK FOR THE HEALTH EFFECT
OF EXPOSURE TO PCB/FS ON HUMAN DIFFUSE LARGE CELL
LYMPHOMA

BACHELOR THESIS

Study Mode:Full-time
Major: Environmental science and management
Faculty:International Programs Office
Batch: 2013-2017

Thai Nguyen, 21/12/2017


DOCUMENTATION PAGE WITH ABSTRACT

Thai Nguyen University of Agriculture and Forestry
Degree Program

Bachelor of Environmental Science and Management

Student name

THAVISACK MIVONGSACK

Student ID

DNT 1253110103

Thesis Title

Potential gene-network for the health effect of
exposure to pcb/fs on human diffuse large cell
lymphoma

Supervisor (s)

Prof. Chun-Yu Chuang,
Associate. Prof. DRTran Van Dien

Abstract:
The thesis describes the Lymphoma is the most top cancers in the worldwide, and the
incidence rises strikingly since the last half of 20thcentury. Lymphoma is a cancer
affecting the immune system; the major risk factor is associated with exposure to
occupational or environmental chemicals. Polychlorinated biphenyls (PCBS) are a
class of organic chemicals, known as congeners that have been used in a variety of
commercial products. PCBs were used in caulking, electronics, fluorescent light
ballasts and other building materials from the 1950s to the late 1970s. Buildings built
or renovated during that time may contain PCBs in caulking and other materials.
PCBare very stable mixtures that are resistant to extreme temperature and pressure.
PCBS were used widely in electrical equipment like capacitors and transformers. They
also were used in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers.

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PCBs have been released into the environment through spills, leaks from electrical and
other equipment, and improper disposal and storage. It is estimated that more than half
of the PCBS produced have been released into the environment. Once in the
environment, PCBS can be transported long distances and they bind strongly to soil
and sediment so they tend to be persistent in the environment. They have been found
in air, water,soil, and sediments throughoutthe world.PCBs can enter the body through
inhalation, ingestion, and dermal routes of exposure. They are readily absorbed but are
slowly metabolized and excreted. In particular, PCBs initially distribute to the liver
and muscle tissues, but eventually accumulate in lipid-rich tissues. This leads to
greater concentrations of PCBS in adipose tissue, breast milk, the liver, and skin. The
data analysis was subsequently performed using Network Analyst, a standard web
browser for network analysis and interactive exploration.

Keywords

TCDD, Furans, DBLCL, bioinformatics, GEO, Array

Express
Number of pages

59

Date of submission

October,2017

Supervisor’s signature

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ACKNOWLEDGEMENT
First of all, we know that knowledge is just only can be proved by our works,
and internship is one of the best opportunity for a student whose can do their first
project before they find their jobs to enroll in the future. Besides that, we are not only
improving ourselves by knowledge in company environment, institute or laboratory
but also making more friends whose are having many experiences in environment, and
it will help us in the near future. From my perspective, this internship is absolutely
needed, helpful and important.
Because of that, and be assigned by the International Programs Office and also
the allowed of Department of Biomedical Engineering and Environmental Sciences
(National TsingHua University, Taiwan). To well done this thesis, I want to express
profound gratitude to Advanced Education Program, the school administrators, the
staffs in Department of Biomedical Engineering and Environmental Sciences, the
staffs of YC laboratory, and particularly my supervisor,Associate. Prof. DRTran Van
Dien and Prof Chun-Yu Chuang whose were always supporting me every single time
I got troubles. I would like to send both of supervisors a warmly thanks for the
supporting me, and for their sacrifice for education, as same as environmental issues in
Taiwan and Vietnam as all countries in the world.
Finally, I would like to say that I had tried my best to finish this thesis in the
best way, I guess. However, to be honest, I partly believe that my thesis still have
some problems because of the limitation of knowledge and reality experiences,
especially in our environmental circumstances these days. It is totally happy if I can

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get feedbacks and comments from you, my Teachers, Professors, and Supervisors, to

finish my thesis in a fantastic way, to get the best results.
Sincerely,
Thai Nguyen October, 2017

THAVISACK MIVONGSACK

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TABLE OF CONTENTS

DOCUMENTATION PAGE WITH ABSTRACT ..........................................................i
ACKNOWLEDGEMENT ............................................................................................. iii
TABLE OF CONTENTS ................................................................................................v
LIST OF FIGURES ...................................................................................................... vii
ABBRIVIATION ...........................................................................................................ix
PART I: INTRODUCTION ............................................................................................1
1.1. Rationale ...................................................................................................................1
1.2. Objectives .................................................................................................................3
PART II:LITERATURE REVIEW .................................................................................4
2.1. Polychlorinated biphenyls (PCBs) ..........................................................................4
2.1.1. Polychlorinated Biphenyls (PCBs) Toxicity .........................................................5
2.1.2. The industrial production of PCB..........................................................................6
2.1.3. PCBs and Environment .........................................................................................7
2.1.4. Health Effects of PCBs ..........................................................................................9
2.2. Lymphoma ..............................................................................................................12
2.3. Biological pathway .................................................................................................13
2.3.1. Diffuse large B cell lymphoma (DLBCL) ...........................................................15
2.4. Gene-network components .....................................................................................17
2.4.1 Gene-network database:Array Express and (GEO)..............................................18

2.4.2. Statistical analysis ...............................................................................................19
3.2. Gene network analysis and Cytoscape for gene-network analysis ........................24

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PART IV: RESULTS AND DISCUSSIONS ................................................................29
4.1. Genetic datasets ......................................................................................................29
4.1.1 Differentially expressed genes .............................................................................32
4.1.2. Gene-network construction of DLBCL and PCBs ..............................................35
4.2. Discussion ...............................................................................................................38
PART V: CONCLUSION AND RECOMMENDATION ............................................41
5.1. Conclusion ..............................................................................................................41
5.2. Recommendation ....................................................................................................42
REFERENCES ..............................................................................................................43

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LIST OF FIGURES

Figure 2.1: Diagram of Polychlorinated Biphenyls (PCBs)(Shoemaker, 2005) .............6
Figure2.2: Polychlorinated biphenyls – levels in foods ................................................11
Figure 2.3: Diffuse large Bcell lymphoma ....................................................................16
Figure 3.1: The flowchart of methodology....................................................................24
Figure 3.2: Cytoscape home page(Shannon P, 2003) ...................................................26
Figure 4.1: Diagram of Gene-network construction of DLBCL & PBCs Sources:
(Rosenwald,2002) ..........................................................................................................37
Figure 4.2: The potential regulatory pathway of NHL progression in response to PCB
exposure Source: (Miller, 2001) ....................................................................................38

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LIST OF TABLES

Table 4.1: Genetics Datasets of DLBCL ............................................................ 30
Table 4.2: Datasets on Array Express used for PCB analysis ............................ 31
Table 4.3: Differentially expressed genes, including –up and down – regulate
genes in Diffuse Large B cell lymphoma compared to normal cells .................. 33
Table 4.4: Differentially expressed genes, including up-and down – regulated
genes activated by PCB compared to control group ........................................... 35

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ABBRIVIATION
ABC

Activated B cell

AML

Acute myeloid leukemia

ALL

Acute lymphoblastic leukemia

B-Cells

B-lymphocytes

B-NHL

Non Hodgkin lymphoma

DLBCL

Diffuse large B cell lymphoma

DMSO

Dimethyl sulfoxide

DEGS

Differentially expressed genes analysis

FL

Follicular lymphoma

FDR

False discovery rate

GEO (NCBI)

Gene expression omnibus National center for

Biotechnology information

GO

Gene Ontology

HL

Hodgkin lymphoma

HIV

Human immunodeficiency virus

ID

Identifier

IARC

International agency for research on cancer

MIAME

Minimum

information

about

microarray

experiment
MAGE-ML

Microarray and Gene Expression Markup
Language

NPL

N-acetylneuraminate pyruvate lyase

NHL

Non Hodgkin lymphoma

PCB

Polychlorinated biphenyls

RS

Reed-Sternberg

SNPs

Single Nocleotide Polymorphisms

T-Cells

T-lymphocytes

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PART I: INTRODUCTION
1.1.

Rationale
Polychlorinated biphenyls, in short PCBs, are a group of man-made

chemicals.PCBs have been used in many different products, including electrical
equipment, surface coatings, inks, adhesives, flame-retardants, and paints. PCBs may
be released into the environment, for instance when waste that contains PCBs is
incinerated or stored in landfills(Morris, 2017).PCBs are probable human carcinogens
and can also cause non-cancer health effects, such as reduced ability to fight
infections, low birth weights, and learning problems. The risks and hazards associated
with PCBs in the Hudson River are a function of the toxicity of PCBs and an
individual's exposure(Hudson, 2016).The most commonly observed health effects in
people exposed to large amounts of PCBs are skin conditions such as acne and rashes.
Studies in exposed workers have shown changes in blood and urine that may indicate
liver damage. PCB exposures in the general population are not likely to result in skin
and liver effects. Most of the studies of health effects of PCBs in the general
population examined children of mothers who were exposed to PCBs(Buford Hwy
NE, 2014).
Polychlorinated biphenyls (PCBs) were powerful carcinogens. A carcinogen is
any substance or agent that tends to produce a cancer. Polychlorinated biphenyls are
found in things such as asbestos and radon. However, we are also forced to consume it
in our foods. There are exposed to many substances at any given time. This includes
those we encounter at work, school, or home, in the food we eat and in the air we

breathe(Jeni, 2011).

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But it’s almost impossible anyone could know precisely what they’ve been exposed to.
PCBs are toxic. They can provoke serious health effects that go beyond cancer. They
can also play a role in hormone disruption, reduced ability to reproduce, skin toxicity,
immune system disorders.
Lymphoma is the most common blood cancer that develop in lymphatic system.
The two main categories of lymphoma are Hodgkin lymphoma and non-Hodgkin
lymphoma (NHL)(Ferlay, 2013). Lymphoma occurs when cells of the immune system
called lymphocytes, a type of white blood cell, grow and multiply uncontrollably.
Cancerous lymphocytes can travel to many parts of the body, including the lymph
nodes, spleen, bone marrow, blood, or other organs, and form a mass called a tumor.
The body has two main types of lymphocytes that can develop into lymphomas: Blymphocytes (B-cells) and T-lymphocytes (T-cells).
Diffuse large cell lymphoma (DLBCL or DLBL) is a cancer of B cells, a type
of white blood cell responsible for producing antibodies. It is the most common type
of non-Hodgkin lymphoma among adults (Clinical, 1997), with an annual incidence of
7–8 cases per 100,000 people per year in the USA and the UK (Morton et al., 19922001). This cancer occurs primarily in older individuals, with a median age of
diagnosis at approximately 70 years of age (Smith et al., 2011), though it can also
occur in children and young adults in rare cases(Smith at el., 2010). DLBCL is an
aggressive tumor which can arise in virtually any part of the body (Kumar et al.,
2009),and the first sign of this illness is typically the observation of a rapidly growing
mass, sometimes associated with B symptoms: fever, weight loss, and night sweats
(Freeman et al, 2012).

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1.2. Objectives
• The aims of the study was tosummarize the health implications associated with
exposure topolychlorinatedbiphenyls (PCBs).
• To identify the potential pathway exposure to dioxin corresponding to DLBCL
• To express the gene number that exposure to dioxin can induce DLBCL and PCBs
• To evaluate diffuse large B-cell lymphoma (DLBCL) and construct regulatory
networks of genes and miRNAs to gradually reveal the underlying mechanisms of
DLBCL development.

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PART II:LITERATURE REVIEW
2.1. Polychlorinated biphenyls (PCBs)
Polychlorinated biphenyls (PCBs) is a group of organic compounds used in the
manufacture of plastics, as lubricants, and dielectric fluids in transformers, in
protective coating for wood, metal and concrete, and in adhesives, wire coating and so
forth (New York, 2003). It can cause a number of different harmfuleffects. They are
highly toxic to aquatic life and persist in the environment for long periods of time.
They can accumulate in food chains and may produce harmful sideeffects at high
concentrations. There are no known natural sources of PCBs in the environment. PCBs
are either oilyliquids or solids and are colorless to light yellow. Some PCBs are
volatile and may exist as avapor in air. They have no known smell or taste(Buford
Hwy NE, 2014). PCBs enter the environment as mixturescontaining a variety of
individual chlorinated biphenyl components, known as congeners, as wellas
impurities. Because the health effects of environmental mixtures of PCBs are difficult
toevaluate, most of the information in thistoxicological profile is about seven types of
PCBmixtures that were commercially produced. These seven kinds of PCB mixtures
include 35% ofall the PCBs commercially produced and 98% of PCBs sold in the
United States since 1970.Some commercial PCB mixtures are known in the United

States by their industrial trade name,Aroclor. For example, the name Aroclor 1254
means that the mixture contains approximately54% chlorine by weight, as indicated by
the second two digits in the name. Because they do not burn easily and are good
insulating materials, PCBs were used widely as coolants and lubricantsin transformers,
capacitors, and other electrical equipment. The manufacture of PCBs stopped inthe

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United States in August 1977 because there was evidence that PCBs build up in
theenvironment and may cause harmful effects. Consumer products that may contain
PCBs includeold fluorescent lighting fixtures, electrical devices or appliances
containing PCB capacitors madebefore PCB use was stopped, old microscope oil, and
old hydraulic oil.
2.1.1. Polychlorinated Biphenyls (PCBs) Toxicity
Since PCBs are found throughout the environment, it is likely that everyone has
been exposed to them. PCBs can enter the body by eating or drinking contaminated
food, through the air we breathe, or by skin contact. PCBs are easily absorbed by the
body and are stored in fatty tissue. PCBs are not eliminated well, so they can
accumulate in the body (Gray et al.,2003; Thrasher and Crawley, 2009).
Most people are exposed to PCBs by eating contaminated fish, meat, and dairy
products. Catfish, buffalo fish, and carp usually have the highest PCB levels. Plants
take up only small amounts of PCBs from the soil, so amounts in grazing animals and
dairy products are generally lower than in fish. Dust contaminated with very small
levels of PCBs may be found on the outer surfaces of fruits and vegetables PCBs do
not dissolve well, so exposure to them from water is usually not a concern. Some
private wells may use old submersible pumps that contain PCB oil. If the pump seal
fails, PCBs can leak into the well and contaminate the drinking water older fluorescent
lights found in schools, offices and homes may still contain transformers or ballasts
that contain PCBs. If the ballasts fail, PCBs can leak out and contaminate exposed

surfaces and the air. PCB levels measured in the air after a light ballast failure can be

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significant. The workplace also may be a source of PCB exposure(Crago et al., 2003,
Etzel, 2006).

Figure 2.1: Diagram of Polychlorinated Biphenyls (PCBs)(Shoemaker, 2005)
PCBs are chemicals formed by attaching one or more chlorine atoms (at the Xs
in Figure 1 above) to a pair of connected benzene rings.Depending on the number and
position of chlorine atoms attached to the biphenyl ring structure, 209 different PCB
congeners can be formed. PCB congeners can be divided into the coplanar, the monoortho-substituted PCBs, and other non-dioxin-like PCBs. The significance of this
designation is that coplanar and some of the mono-ortho-substituted PCBs have
dioxin-like toxicological effects(Shoemaker, 2005).
2.1.2. The industrial production of PCB
PCBs were used for many different industrial purposes, including the afore
mentioned electrical industry and: Hydraulic fluids; casting wax; carbonless carbon
paper; compressors; heat transfer systems; plasticizers; pigments; adhesives; liquid
cooled electric motors; fluorescent light ballasts. There is little wonder that this group
of chemicals was so readily accepted.
One of the qualities that make PCBs so desirable is one of the characteristics
that make PCBs so hazardous to the environment. The high thermal and chemical
resistance of PCBs means that they do not readily break down when exposed to heat
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orchemical treatment. This is a very desirable trait for lubricants. However, since
PCBs do not break down they remain in the environment and continue to build up as
more are introduced into the environment. Worms consume organic matter

contaminated with PCBs, and small fishes eat the worms. Small fish are then eaten by
larger fish, and perhaps the large fish are eaten by an eagle. Worms may only live for a
short time, but eagles live for a long time. They continue to eat lots of large fish that
ate lots of small fish that ate lots of contaminated worms. Over a lifetime, the PCB
concentration in the fatty tissue of the eagle would continue to increase as it ate more
and more contaminated fish. This accumulation of a chemical in animals at the top of
the food chain is known as bioaccumulation. If the chemical happens to be toxic, the
consequences become obvious.
2.1.3. PCBs and Environment
Before 1977, PCBs entered the air, water, and soil during their manufacture
and use in theUnited States. Wastes that contained PCBs were generated at that time,
and these wastes wereoften placed in landfills. PCBs also entered the environment
from accidental spills and leaksduring the transport of the chemicals, or from leaks or
fires in transformers, capacitors, or otherproducts containing PCBs. Today, PCBs can
still be released into the environment from poorlymaintained hazardous waste sites
that contain PCBs; illegal or improper dumping of PCBwastes, such as old transformer
fluids; leaks or releases from electrical transformers containingPCBs; and disposal of
PCB-containing consumer products into municipal or other landfills notdesigned to
handle hazardous waste. PCBs may be released into the environment by the burningof
some wastes in municipal and industrial incinerators.Once in the environment, PCBs

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do not readily break down and therefore may remain for verylong periods of time.
They can easily cycle between air, water, and soil. For example, PCBs canenter the air
by evaporation from both soil and water. In air, PCBs can be carried long distancesand
have been found in snow and sea water in areas far away from where they were
released intothe environment, such as in the arctic. As a consequence, PCBs are found
all over the world. Ingeneral, the lighter the type of PCBs, the further they may be

transported from the source ofcontamination. PCBs are present as solid particles or as
a vapor in the atmosphere. They willeventually return to land and water by settling as
dust or in rain and snow. In water, PCBs maybe transported by currents, attach to
bottom sediment or particles in the water, and evaporate intoair. Heavy kinds of PCBs
are more likely to settle into sediments while lighter PCBs are morelikely to evaporate
to air. Sediments that contain PCBs can also release the PCBs into thesurrounding
water. PCBs stick strongly to soil and will not usually be carried deep into the soilwith
rainwater. They do not readily break down in soil and may stay in the soil for months
oryears; generally, the more chlorine atoms that the PCBs contain, the more slowly
they breakdown.Evaporation appears to be an important way by which the lighter
PCBs leave soil. As agas, PCBs can accumulate in the leaves and above-ground parts
of plants and food crops.PCBs are taken up into the bodies of small organisms and fish
in water. They are also taken upby other animals that eat these aquatic animals as food.
PCBs especially accumulate in fish andmarine mammals (such as seals and whales)
reaching levels that may be many thousands oftimes higher than in water. PCB levels
are highest in animals high up in the food chain.

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Environmental contamination from PCBs has been caused by accidental
releases, careless disposal practices, and leaks from industrial facilities or chemical
waste-water disposal sites. PCBs degrade very slowly, are cycled and transported
within the ecosystem, and bioaccumulate as they move up the food chain.
Once released into the environment, PCBs adsorb strongly to soil and sediment.
As a result, these compounds tend to persist in the environment, with half-lives for
most congeners ranging from months to years. PCBs leach from soil slowly,
particularly the more highly chlorinated congeners, and translocate to plants via soil
insignificantly. Cycling of PCBs through the environment involves volatilization from
land and water surfaces into the atmosphere, with subsequent removal from the

atmosphere by wet or dry deposition, then revolatilization. In the general population,
inhalation of these airborne PCBs is one route of exposure, in addition to the food
source of exposure to PCBs.
Once released into the environment, PCBs may undergo all of the volatilization
from land and water surfaces into the atmospheres, biotransformation into more
complex undefined mixtures, fast degradation within the ecosystem and strong
adsorption to soil and sediment.
2.1.4. Health Effects of PCBs
A growing number of studies have found serious health effects from exposure
to PCBs. PCBs are likely to cause cancer and are classified as a “probable carcinogen”
by the federal Environmental Protection Agency and the International Agency for
Research on Cancer. In addition, a study found children’s risk of developing acute
lymphocytic leukemia, increased by two-fold when PCBs were detected in the dust of

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a room in which the child spent a significant amount of time(Ward M H, 2009). People
with potentially high exposures to PCBs include: Recreational and subsistence fishers
who typically consume larger quantities of locally caught fish than the general
population, Children with in utero and lactational exposure to PCBs from mothers who
eat large quantities of contaminated fish during pregnancy and while nursing,Certain
farmers and their families who consume PCB-contaminated food via their own farmraised beef and dairy cattle, andpeople living near incinerators, other PCB-disposal
facilities, or NPL hazardous waste sites where PCBs have been detected (Buford Hwy
NE A. , 2016).
PCBs can enter human cells and tissues when contaminated air is breathed in,
when contaminated food enters the digestive system, or through contact with the skin.
Tests on laboratory animals show that PCBs are readily absorbed through the digestive
tract when swallowed, and to a lesser extent through the skin. The main PCB
elimination routes are through the faeces, urine, and breast milk. Once in the

gastrointestinal tract, ingested PCBs diffuse across cell membranes and enter blood
vessels and the lymphatic system. PCBs, especially those that contain a greater number
of chlorine atoms, are readily soluble in fats and thus tend to accumulate in fat-rich
tissues such as the liver, brain and skin.In mothers, PCBs have also been found to pass
into the placenta, umbilical cord blood, and breast milk. PCBs can undergo different
transformations in the body and then either be stored in certain tissues or excreted.
Transformations that lead to accumulation,PCBs can easily be transformed into
persistent metabolites that are not readily excreted and that can accumulate in

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specifictissues and body fluids. The biological half-life of these persistent metabolites
depends on the structure of the original PCB.
Transformations that lead to excretion, PCBs can leave the blood and enter
tissues very rapidly and be transformed into water-soluble substances. These can
combine with glutathione and glucuronic acid, that are naturally present in the body,
forming a substance that is then excreted in urine and feces. The speed of this process
depends on the number and position of chlorine atoms of the original PCB. It is, for
instance, slower when there are more chlorine atoms on both phenyl rings and faster if
there are two carbon atoms without any attached chlorine atoms next to each other.
In a case where both children and their mothers were exposed to PCBs through
their diet, levels of PCBs in blood dropped more rapidly in the children. This may be
partly explained by the children’s growth, as their increasing tissue mass may lower
the PCB concentration in blood due to dilution, rather than elimination.

Figure2.2: Polychlorinated biphenyls – levels in foods
Source: USDA Nutrient Database for Standard Reference, Release 16 (2003)

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This graph shows the absolute amount of polychlorinated biphenyls in various
foods. It is taken from a FDA market basket study

2.2. Lymphoma
Lymphoma is a type of cancer that begins in infection-fighting cells of the
immune system, called lymphocytes. The two main types of lymphoma are Hodgkin
lymphoma (HL) and non-Hodgkin lymphoma (NHL). It isonly possible to determine
the difference between HL and NHL under a microscope. In HL, a particular cell
called the Reed-Sternberg (RS) cell is found. NHL is much more common than HL
about 90% of lymphoma is NHL. According to the America Cancer Society, the 5 year
survival rate for HL is 85%, with a 10 year survival rate of 81%. There are many
different forms of NHL, and prognoses vary, but HL tends to be easier to treat. Nearly
40% of NHL diagnosed cases are at stage iv, which are more likely to spread and not
as predictable in terms of their progression.
NHL incidence rate has increased markedly in recent year. International
Agency for Research on Cancer (IARC) declared the incidence rate and the mortality
rate of NHL were 9.8 and 3.5 per 100,000 populations during 1990 to 2010 in forty
countries of Europe. In Taiwan, from 2000 to 2012, the standardized cancer incidence
rate of NHL was from 4.03 per 100,000 populations rising to 7.23. NHL is a diverse
group of cancers originating in the cells of immune system, including B-lymphocytes,
t-lymphocytes and natural killer cells. Most types of NHL from B-lymphocytes, called
B-cell non-Hodgkin lymphoma (B-NHL). Types of NHL vary significantly in their
severity, from indolent (slow-growing) to vary aggressive (fast-growing) types. Based
on a WHO classification system, more than 30 different subtypes have been

12

identified.The most common histologic subtype of NHL is diffuse large B-cell
lymphoma (DLBCL), which is an aggressive, fast-growing lymphoma. Follicular
lymphoma (FL) is the second most common, which is an indolent, slow-growing
lymphoma. Several epidemiologic studies explored that the risk factors of NHL
include human immunodeficiency virus (HIV) infection, other viral and bacterial
infections, and increased use of immunosuppressive drugs, changes in diet and
lifestyle, and exposure to various chemicals. Although the descriptive epidemiology of
NHL has been well characterized using population-based cancer registry data, the
etiology of NHL is less well understood.
2.3. Biological pathway
A biological pathway is a series of actions among molecules in a cell that leads
to a certain product or a change in the cell. Such a pathway can trigger the assembly of
new molecules, such as a fat or protein. Pathways can also turn genes on and off, or
spur a cell to move.
For your body to develop properly and stay healthy, many things must work
together at many different levels - from organs to cells to genes. From both inside and
outside the body, cells are constantly receiving chemical cues prompted by such things
as injury, infection, stress or even the presence or lack of food. To react and adjust to
these cues, cells send and receive signals through biological pathways. The molecules
that make up biological pathways interact with signals, as well as with each other, to
carry out their designated tasks.
Biological pathways can act over short or long distances. For example, some
cells send signals to nearby cells to repair localized damage, such as a scratch on a

13


knee. Other cells produce substances, such as hormones, that travel through the blood
to distant target cells. These biological pathways control a person's response to the
world. For example, some pathways subtly affect how the body processes drugs, while

others play a major role in how a fertilized egg develops into a baby. Other pathways
maintain balance while a person is walking, control how and when the pupil in the eye
opens or closes in response to light, and affect the skin's reaction to changing
temperature. Biological pathways do not always work properly. When something goes
wrong in a pathway, the result can be a disease such as cancer or diabetes.
Researchers have discovered many important biological pathways through
laboratory studies of cultured cells, bacteria, fruit flies, mice and other organisms.
Many of the pathways identified in these model systems are the same as, or are similar
to, counterparts in humans. Still, many biological pathways remain to be discovered. It
will take years of research to identify and understand the complex connections among
all the molecules in all biological pathways, as well as to understand how these
pathways work together.
Finding out what pathway is involved in a disease - and identifying which step
of the pathway is affected in each patient may lead to more personalized strategies for
diagnosing, treating and preventing disease. Researchers currently are using
information about biological pathways to develop new and more effective drugs. It
likely will take some time before we routinely see specifically designed drugs that are
based on information about biological pathways. However, doctors are already
beginning to use pathway information to choose and combine existing drugs more
effectively(Español, August 27, 2015).

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2.3.1. Diffuse large B cell lymphoma (DLBCL)
The lymphoma organs include the bone marrow, thymus, spleen, and lymph
nodes. These help to fight infection throughout the body. The organs of the lymphatic
systems are connected by a network of lymphatic and blood vessels. Lymphatic fluid
contains white blood cells called lymphocytes.
There are two primary types of lymphocytes: B cells and T cells. Diffuse large

B cell lymphoma (DLBCL) is a cancer of B lymphocytes. Almost all lymphocytes
begin growing in the bone marrow or lymph nodes. T cells leave the bone marrow
before they are completely matured, and finish maturing in the thymus gland. B cells
instead continue to develop and mature in the bone marrow and lymph nodes. In
DLBCL, the abnormal B cell lymphocytes are larger than normal, and they have
stopped responding to signals that usually limit the growth and reproduction of cells.
This subtype of lymphoma is called diffuse large B cell because of the way the
malignant large B cells are distributed within the lymph nodes when examined with a
microscope.
There are different varieties of DLBCL that can be identified by performing
advanced tests on the lymph node specimen. Particular varieties of DLBCL may be
more likely to respond to certain treatments. Terms that may be used to describe the
varieties of DLBCL include the following: Germinal center B cell type (GCB),
Activated B cell type (ABC), double hit lymphoma.
DLBCL can either develop as a transformation from a less aggressive form of
lymphoma or as a first occurrence of lymphoma.

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