Instructions

Please read and follow these instructions carefully. Make sure you
understand what you have to do before attempting to complete this
assignment.

The purpose of this assignment is to get you to synthesise information about cancer and epigenetics gleaned
from the lecture videos, and the following scientific review paper and article in the popular press:

 Magazine article: (2012, 7th April). Cancer's epicentre. The Economist.

 Review article: Hassler MR, Egger G. (2012). Epigenomics of cancer - emerging new concepts.
Biochimie, 94(11):2219-30

Part of being a good scientist is to read widely, attend talks, understand the key concepts and in turn
communicate these concepts to others. During this writing assignment you will get a taste of what this
experience is like.

The writing assignment is broken down into four (4) main questions. Each question includes specific details
to help you identify the critical points you should be making and ensure you meet the grading criteria. Good
scientific writing is clear and concise, so there is a word limit for each question. Your answers should be
written in prose form and not bullet points or lists.

You will need to complete all four parts and enter your answers in the ‘My submission’ section (see
above tab).

Review criteriamenos
You will need to review five (5) of your peers' work as part of this assignment after you have made your own
submission.

Please remember that not all students come from an English speaking background. Focus on whether the
relevant points have been clearly stated and not on the quality and sophistication of the language.

Questions 1 - 4
Question 1
Describe how DNA methylation is altered in cancer (maximum 300 words). In your answer include the
following points:

 Describe the normal function of DNA methylation at CpG islands

 Describe how DNA methylation of CpG islands is disrupted in cancer
 Explain how disruption of DNA methylation at CpG islands contributes to cancer
 Describe the normal function of DNA methylation in intergenic regions and repetitive elements

En el ADN existen dinucleótidos CpG que son la unión de citosina con guanina. Estos dinucleótidos se
encuentran en mayor medida en las regiones promotoras de genes, zonas de inicio de la transcripción
génica. En algunos casos la citosina está metilada formando 5′-metil-citosina. Esta metilación puede ser
normal a lo largo del ADN, pero en las zonas de islas CpG, si no hay metilación en esas zonas es un
indicador de que el sitio de transcripción se encuentra activado. Cuando estas islas CpG presentan una
elevada metilación se puede producir el silenciamiento de la transcripción del gen. En ciertos tipos de
genes, llamados supresores de tumores, una metilación excesiva en su región promotora, o sea las islas
CpG, puede suprimir la transcripción, evitando así que se expresen los genes de esa zona. Estos genes se
encargan de evitar errores en las células y su inactivación puede llegar a producir una división
descontrolada produciendo cáncer. En el 98% del genoma, las islas CpG aparecen una vez cada 100
dinucleótidos y se encuentran muy metilados con objeto de estructurar la cromatina nuclear en un estado
represivo que impida la transcripción de regiones poco útiles y potencialmente peligrosas del ADN, tales
como las secuencias que son repetitivas.

There are CpG dinucleotides that are the union of cytosine with guanine in DNA. These dinucleotides
are greater in the promoter regions of genes, gene transcription starting zones. In some cases the
cytosine is methylated forming 5′-methyl-cytosine. This methylation can be normal along the DNA,
but in areas of CpG Islands, if there is no methylation in these areas is an indicator that the site of
transcription is activated. When these CpG Islands have a high methylation can occur the silencing of
the transcription of the gene. In certain types of genes, called suppressor of tumors, an excessive
methylation in the promoter region, or CpG Islands, can suppress transcription, thus preventing
expressed genes in that area. These genes are responsible for avoiding mistakes in cells and
inactivation can cause an uncontrolled division producing cancer. In 98% of the genome, CpG islands
appear once every 100 dinucleotides and are very methylated with the aim of structuring the nuclear
chromatin in a repressive State that prevents transcription of unhelpful and potentially dangerous
regions of DNA, such as sequences that are repeated. Intergenic regions and repetitive elements use
to have their promotors methylated. When these promotors are unmethylated these regions are
 expressed and some genes in this zone should not to be expressed, if that occurs it will cause
serious diseases.

Question 2
Describe how disruption of imprinting can contribute to cancer, using the example of the H19/Igf2 cluster
(maximum 200 words). In your answer include the following points:

 Describe the methylation pattern of the paternal allele and how this determines Igf2 expression status
 Describe the methylation pattern of the maternal allele and how this determines Igf2 expression status
 Describe how imprinting at the H19/Igf2 cluster is disrupted in Wilm’s tumour
 Explain how disrupting imprinting at the H19/Igf2 cluster contributes to cancer.

In cancer, aberrant patterns of DNA methylation (hypermethylation or hypomethylation) can also be

observed at imprint control regions, leading to the loss of imprinting. A clear example is the disruption
of the imprinting at the H19/Igf2 cluster. In normal cells, Igf2 and H19 genes are imprinted in mammals:
Igf2 is a growth factor expressed exclusively by the paternal allele and the H19 is transcribed from the
maternal allele. This is controlled by an imprinted-control region (ICR) two kilobases upstream of H19.
This region is methylated on paternal allele but is unmethylated in maternal allele. When maternal ICR is
unmethylated, joins with the protein CTCF, that insulates Igf2 from downstream enhancers and blocks
the expression of Igf2 from the maternal allele. In contrast, in paternal allele, the ICR is methylated and
cannot bind to CTCF, in consequence downstream enhancers can activate the expression of Igf2 from
paternal allele and inhibits expression of H19. However, when maternal ICR is hypermethylated, like in
Wilm´s tumour, can act as the paternal allele and express Igf2 too. In consequence the overexpression of
this growth factor stimulates proliferation of cancer cells and thus contributes to various human cancers
including Wilm´s tumour, hepatoblastoma, colorectal and breast carcinomas.

En las células normales, se expresan lgf2 y H19. Igf2 es un factor de crecimiento que es expresado solo
por el alelo paterno y el H19 es expresado desde el alelo maternal. Esto es controlado por una región de
control de impreso ICR la cual está metilada en el alelo paterno, pero no en el materno. Si ICR no se
metila en el alelo materno, se une a la proteína CTCF, provocando que no se exprese Igf2. En el alelo
paterno ICR sí está metilado por lo que se expresa lgf2.

Question 3
The Economist article “Cancer’s epicentre” describes several drugs that affect epigenetic processes. Explain
how Decitabine may be used to treat cancer, with reference to effects on the epigenome (maximum 150
words). In your answer include the following points:
  Identify the class of epigenetic inhibitors that Decitabine belongs to
 Describe the impact of Decitabine on DNA methylation
 Describe how Decitabine can have an anti-tumour effect.

Decitabine pertenece a la clase de inhibidores de metiltransferasas de DNA. De los diferentes tipos de

metiltransferasas que hay, Decitabine inhibe a DNMT1 provocando un bloqueo irreversible de DNMT1.
Este bloqueo es provocado porque tiene un átomo de nitrógeno heterocíclico en el lugar de la metilación
de los residuos de citosina. Se ha reportado que esta droga tiene un efecto antitumoral ya que se cree que el
silenciamiento en el cromosoma 11q13 desempeña un papel en el origen de estos tumores. Si Decitabine
inhibe DNMT1 impedirá el silenciamiento de este cromosoma y restaurará la expresión de este teniendo el
efecto antitumoral en carcinoma adrenocortical.

Decitabine belongs to the class of inhibitors of DNA methyltransferases. Different types of

methyltransferases that exist, Decitabine inhibits DNMT1 causing an irreversible blockade of DNMT1. This
blockade is caused because you have a heterocyclic nitrogen atom in place of the methylation of cytosine
residues (Goffin & Eisenhauer, 2002). It is reported that this drug has an Antitumor effect since it is
believed that the silencing in chromosome 11q13 plays a role in the origin of these diseases. If Decitabine
inhibits DNMT1 will prevent the silencing of this chromosome and restore the expression of this having
Antitumor effect in adrenocortical carcinoma.

Question 4
Dr Stephen Baylin speculates in the Economist article that "epigenetic drugs altered the tumour cells in some
lasting way that made them more susceptible to standard chemotherapy." How can drugs that alter DNA
methylation have effects that last beyond the period of drug treatment? Discuss whether there are any periods
of development when you would avoid treating patients with such drugs (maximum 200 words). In your
answer include the following points:

 Describe how altering DNA methylation can have enduring effects on the epigenome
 Define what is meant by a sensitive period
 Identify sensitive periods of development
 Explain why treating patients during sensitive periods would be inadvisable.

La metilación de ADN es una marca epigenética que es mitóticamente heredable, así que esas alteraciones
pasan a las células hijas provocando que el efecto sea duradero. El periodo sensitivo está definido por los
sucesos ocurridos antes de que sean definidos y estabilizados mitóticamente los cambios epigenéticos y la
metilación de ADN en células somáticas. Tratar a pacientes con las drogas ya mencionadas podría
provocar modificaciones epigenéticas aberrantes y silenciar en el caso de los inhibidores de
metiltransferasas que inhiban la expresión de un gen necesario y como esto es mitóticamente heredable o
 sea que estos patrones epigenéticos se transmiten por divisiones celulares, pasarían a las células hijas
influyendo en el desarrollo de enfermedades.

DNA methylation is an epigenetic mark that is mitotically heritable, so these changes are inherited to
daughter cells causing the effect is lasting. The sensitive period is defined by the events occurred before
epigenetic changes and DNA methylation in somatic cells are defined and stabilize mitotically. Treat
patients with the aforementioned drugs may cause aberrant epigenetic modifications and silence, in the
case of inhibitors of methyltransferases, the expression of a gene necessary. And as this is mitotically
heritable, ie these epigenetic marks are transmitted by cell divisions to daughter cells would influence the
development of cancer diseases.