£1,000,000
£750,000

Update from Chris Mitchell – May 2007

Abnormal Genes in Children’s Cancers

Everything about an individual – from the colour of their eyes to their fingerprint patterns – is encoded by genes, which themselves consist of varying lengths of DNA. Genes, in turn are packaged into chromosomes, which, given a powerful enough microscope and appropriate conditions can be seen within each cell as worm like structures. Each human has 23 pairs of chromosomes, half of each pair being inherited from their mother and the other half of each pair inherited from their father. By way of example, one of the pairs of chromosomes determines, amongst other things, the sex of the individual, with two XX chromosomes determining a female and the XY combination a male, reflecting the function of some of the genes on these particular chromosomes. When a cell divides, the number of chromosomes briefly doubles up so that the two new cells end up with the full set of 23 pairs of chromosomes.

Sometimes, during the division of a cell, the chromosomes break into two parts. The body has the necessary repair mechanisms to deal with this sort of damage but occasionally the process goes awry and the bits of broken chromosomes do not find their proper partners and end up on another chromosome. This type of abnormality is known as a chromosome translocation. The very first example of this sort of abnormality was first seen in a condition called chronic myeloid leukaemia, where the bits of chromosomes 9 and 22 get jumbled to produce what is known as the Philadelphia chromosome, after the city where it was first described in the early 1960s. Since then there have been a range of similar abnormalities described in a wide range of cancers. Our particular interest is focussed on the translocation between chromosomes 2 and 13 (written as “t(2;13)”) seen in a childhood tumour called rhabdomyosarcoma, which is a tumour of striped muscle. At the actual breakpoint of the chromosome will be a gene – now in two parts. When incorrectly reassembled there are now two hybrid genes which will not be under normal control and which will be making abnormal proteins – proteins which must have some effects on the cell which result in what we recognise as cancer.

This abnormality was first described the late 1980s and is now known to be associated with a poor prognosis for the patients whose tumour contains it. From a scientific view, the useful thing about a translocation is that it enables one to pinpoint the genes that are involved, which in turn allows the examination of the pathways those genes would normally be a part of. In the case of the t(2;13) we know that the two normal genes involved are called Pax 3 (for Paired boX 3) and FKHR (for FoRKHead) and that they have normal functions in controlling the migration and maturation of skeletal muscle. One of the hybrid genes will contain the first part of Pax3 and tail end of FKHR, and the other hybrid will be the converse.

We have previously described a method by which the abnormal repair might take place. Over the past few years we have been working to understand the effects of the abnormal genes. We have been able to determine that the presence of these two hybrid genes leads to the abnormal regulation of a large number of other genes within the affected cell. We have chosen to focus on a few of these abnormally regulated genes and in particular on those genes that might determine the ability of a cell to migrate through the body.

During normal development of a fetus, for example, the muscle cells start in the centre of the body and migrate out into the developing limb buds to form, ultimately the muscles that are present in fully developed arms and legs. This process is akin to that which occurs when cancer cells spread through the body to form secondary tumours. Understanding this process might begin to provide the insights needed to develop treatment, which could control or prevent the spread of cancer cells.

Obviously there is a long way to go from a laboratory experiment whe

Everything about an individual – from the colour of their eyes to their fingerprint patterns – is encoded by genes, which themselves consist of varying lengths of DNA. Genes, in turn are packaged into chromosomes, which, given a powerful enough microscope and appropriate conditions can be seen within each cell as worm like structures. Each human has 23 pairs of chromosomes, half of each pair being inherited from their mother and the other half of each pair inherited from their father. By way of example, one of the pairs of chromosomes determines, amongst other things, the sex of the individual, with two XX chromosomes determining a female and the XY combination a male, reflecting the function of some of the genes on these particular chromosomes. When a cell divides, the number of chromosomes briefly doubles up so that the two new cells end up with the full set of 23 pairs of chromosomes.

Sometimes, during the division of a cell, the chromosomes break into two parts. The body has the necessary repair mechanisms to deal with this sort of damage but occasionally the process goes awry and the bits of broken chromosomes do not find their proper partners and end up on another chromosome. This type of abnormality is known as a chromosome translocation. The very first example of this sort of abnormality was first seen in a condition called chronic myeloid leukaemia, where the bits of chromosomes 9 and 22 get jumbled to produce what is known as the Philadelphia chromosome, after the city where it was first described in the early 1960s. Since then there have been a range of similar abnormalities described in a wide range of cancers. Our particular interest is focussed on the translocation between chromosomes 2 and 13 (written as “t(2;13)”) seen in a childhood tumour called rhabdomyosarcoma, which is a tumour of striped muscle. At the actual breakpoint of the chromosome will be a gene – now in two parts. When incorrectly reassembled there are now two hybrid genes which will not be under normal control and which will be making abnormal proteins – proteins which must have some effects on the cell which result in what we recognise as cancer.

This abnormality was first described the late 1980s and is now known to be associated with a poor prognosis for the patients whose tumour contains it. From a scientific view, the useful thing about a translocation is that it enables one to pinpoint the genes that are involved, which in turn allows the examination of the pathways those genes would normally be a part of. In the case of the t(2;13) we know that the two normal genes involved are called Pax 3 (for Paired boX 3) and FKHR (for FoRKHead) and that they have normal functions in controlling the migration and maturation of skeletal muscle. One of the hybrid genes will contain the first part of Pax3 and tail end of FKHR, and the other hybrid will be the converse.

We have previously described a method by which the abnormal repair might take place. Over the past few years we have been working to understand the effects of the abnormal genes. We have been able to determine that the presence of these two hybrid genes leads to the abnormal regulation of a large number of other genes within the affected cell. We have chosen to focus on a few of these abnormally regulated genes and in particular on those genes that might determine the ability of a cell to migrate through the body.

During normal development of a fetus, for example, the muscle cells start in the centre of the body and migrate out into the developing limb buds to form, ultimately the muscles that are present in fully developed arms and legs. This process is akin to that which occurs when cancer cells spread through the body to form secondary tumours. Understanding this process might begin to provide the insights needed to develop treatment, which could control or prevent the spread of cancer cells.

Obviously there is a long way to go from a laboratory experiment whe

Everything about an individual – from the colour of their eyes to their fingerprint patterns – is encoded by genes, which themselves consist of varying lengths of DNA. Genes, in turn are packaged into chromosomes, which, given a powerful enough microscope and appropriate conditions can be seen within each cell as worm like structures. Each human has 23 pairs of chromosomes, half of each pair being inherited from their mother and the other half of each pair inherited from their father. By way of example, one of the pairs of chromosomes determines, amongst other things, the sex of the individual, with two XX chromosomes determining a female and the XY combination a male, reflecting the function of some of the genes on these particular chromosomes. When a cell divides, the number of chromosomes briefly doubles up so that the two new cells end up with the full set of 23 pairs of chromosomes.

Sometimes, during the division of a cell, the chromosomes break into two parts. The body has the necessary repair mechanisms to deal with this sort of damage but occasionally the process goes awry and the bits of broken chromosomes do not find their proper partners and end up on another chromosome. This type of abnormality is known as a chromosome translocation. The very first example of this sort of abnormality was first seen in a condition called chronic myeloid leukaemia, where the bits of chromosomes 9 and 22 get jumbled to produce what is known as the Philadelphia chromosome, after the city where it was first described in the early 1960s. Since then there have been a range of similar abnormalities described in a wide range of cancers. Our particular interest is focussed on the translocation between chromosomes 2 and 13 (written as “t(2;13)”) seen in a childhood tumour called rhabdomyosarcoma, which is a tumour of striped muscle. At the actual breakpoint of the chromosome will be a gene – now in two parts. When incorrectly reassembled there are now two hybrid genes which will not be under normal control and which will be making abnormal proteins – proteins which must have some effects on the cell which result in what we recognise as cancer.

This abnormality was first described the late 1980s and is now known to be associated with a poor prognosis for the patients whose tumour contains it. From a scientific view, the useful thing about a translocation is that it enables one to pinpoint the genes that are involved, which in turn allows the examination of the pathways those genes would normally be a part of. In the case of the t(2;13) we know that the two normal genes involved are called Pax 3 (for Paired boX 3) and FKHR (for FoRKHead) and that they have normal functions in controlling the migration and maturation of skeletal muscle. One of the hybrid genes will contain the first part of Pax3 and tail end of FKHR, and the other hybrid will be the converse.

We have previously described a method by which the abnormal repair might take place. Over the past few years we have been working to understand the effects of the abnormal genes. We have been able to determine that the presence of these two hybrid genes leads to the abnormal regulation of a large number of other genes within the affected cell. We have chosen to focus on a few of these abnormally regulated genes and in particular on those genes that might determine the ability of a cell to migrate through the body.

During normal development of a fetus, for example, the muscle cells start in the centre of the body and migrate out into the developing limb buds to form, ultimately the muscles that are present in fully developed arms and legs. This process is akin to that which occurs when cancer cells spread through the body to form secondary tumours. Understanding this process might begin to provide the insights needed to develop treatment, which could control or prevent the spread of cancer cells.

Obviously there is a long way to go from a laboratory experiment whe

Everything about an individual – from the colour of their eyes to their fingerprint patterns – is encoded by genes, which themselves consist of varying lengths of DNA. Genes, in turn are packaged into chromosomes, which, given a powerful enough microscope and appropriate conditions can be seen within each cell as worm like structures. Each human has 23 pairs of chromosomes, half of each pair being inherited from their mother and the other half of each pair inherited from their father. By way of example, one of the pairs of chromosomes determines, amongst other things, the sex of the individual, with two XX chromosomes determining a female and the XY combination a male, reflecting the function of some of the genes on these particular chromosomes. When a cell divides, the number of chromosomes briefly doubles up so that the two new cells end up with the full set of 23 pairs of chromosomes.

Sometimes, during the division of a cell, the chromosomes break into two parts. The body has the necessary repair mechanisms to deal with this sort of damage but occasionally the process goes awry and the bits of broken chromosomes do not find their proper partners and end up on another chromosome. This type of abnormality is known as a chromosome translocation. The very first example of this sort of abnormality was first seen in a condition called chronic myeloid leukaemia, where the bits of chromosomes 9 and 22 get jumbled to produce what is known as the Philadelphia chromosome, after the city where it was first described in the early 1960s. Since then there have been a range of similar abnormalities described in a wide range of cancers. Our particular interest is focussed on the translocation between chromosomes 2 and 13 (written as “t(2;13)”) seen in a childhood tumour called rhabdomyosarcoma, which is a tumour of striped muscle. At the actual breakpoint of the chromosome will be a gene – now in two parts. When incorrectly reassembled there are now two hybrid genes which will not be under normal control and which will be making abnormal proteins – proteins which must have some effects on the cell which result in what we recognise as cancer.

This abnormality was first described the late 1980s and is now known to be associated with a poor prognosis for the patients whose tumour contains it. From a scientific view, the useful thing about a translocation is that it enables one to pinpoint the genes that are involved, which in turn allows the examination of the pathways those genes would normally be a part of. In the case of the t(2;13) we know that the two normal genes involved are called Pax 3 (for Paired boX 3) and FKHR (for FoRKHead) and that they have normal functions in controlling the migration and maturation of skeletal muscle. One of the hybrid genes will contain the first part of Pax3 and tail end of FKHR, and the other hybrid will be the converse.

We have previously described a method by which the abnormal repair might take place. Over the past few years we have been working to understand the effects of the abnormal genes. We have been able to determine that the presence of these two hybrid genes leads to the abnormal regulation of a large number of other genes within the affected cell. We have chosen to focus on a few of these abnormally regulated genes and in particular on those genes that might determine the ability of a cell to migrate through the body.

During normal development of a fetus, for example, the muscle cells start in the centre of the body and migrate out into the developing limb buds to form, ultimately the muscles that are present in fully developed arms and legs. This process is akin to that which occurs when cancer cells spread through the body to form secondary tumours. Understanding this process might begin to provide the insights needed to develop treatment, which could control or prevent the spread of cancer cells.

Obviously there is a long way to go from a laboratory experiment whe

Everything about an individual – from the colour of their eyes to their fingerprint patterns – is encoded by genes, which themselves consist of varying lengths of DNA. Genes, in turn are packaged into chromosomes, which, given a powerful enough microscope and appropriate conditions can be seen within each cell as worm like structures. Each human has 23 pairs of chromosomes, half of each pair being inherited from their mother and the other half of each pair inherited from their father. By way of example, one of the pairs of chromosomes determines, amongst other things, the sex of the individual, with two XX chromosomes determining a female and the XY combination a male, reflecting the function of some of the genes on these particular chromosomes. When a cell divides, the number of chromosomes briefly doubles up so that the two new cells end up with the full set of 23 pairs of chromosomes.

Sometimes, during the division of a cell, the chromosomes break into two parts. The body has the necessary repair mechanisms to deal with this sort of damage but occasionally the process goes awry and the bits of broken chromosomes do not find their proper partners and end up on another chromosome. This type of abnormality is known as a chromosome translocation. The very first example of this sort of abnormality was first seen in a condition called chronic myeloid leukaemia, where the bits of chromosomes 9 and 22 get jumbled to produce what is known as the Philadelphia chromosome, after the city where it was first described in the early 1960s. Since then there have been a range of similar abnormalities described in a wide range of cancers. Our particular interest is focussed on the translocation between chromosomes 2 and 13 (written as “t(2;13)”) seen in a childhood tumour called rhabdomyosarcoma, which is a tumour of striped muscle. At the actual breakpoint of the chromosome will be a gene – now in two parts. When incorrectly reassembled there are now two hybrid genes which will not be under normal control and which will be making abnormal proteins – proteins which must have some effects on the cell which result in what we recognise as cancer.

This abnormality was first described the late 1980s and is now known to be associated with a poor prognosis for the patients whose tumour contains it. From a scientific view, the useful thing about a translocation is that it enables one to pinpoint the genes that are involved, which in turn allows the examination of the pathways those genes would normally be a part of. In the case of the t(2;13) we know that the two normal genes involved are called Pax 3 (for Paired boX 3) and FKHR (for FoRKHead) and that they have normal functions in controlling the migration and maturation of skeletal muscle. One of the hybrid genes will contain the first part of Pax3 and tail end of FKHR, and the other hybrid will be the converse.

We have previously described a method by which the abnormal repair might take place. Over the past few years we have been working to understand the effects of the abnormal genes. We have been able to determine that the presence of these two hybrid genes leads to the abnormal regulation of a large number of other genes within the affected cell. We have chosen to focus on a few of these abnormally regulated genes and in particular on those genes that might determine the ability of a cell to migrate through the body.

During normal development of a fetus, for example, the muscle cells start in the centre of the body and migrate out into the developing limb buds to form, ultimately the muscles that are present in fully developed arms and legs. This process is akin to that which occurs when cancer cells spread through the body to form secondary tumours. Understanding this process might begin to provide the insights needed to develop treatment, which could control or prevent the spread of cancer cells.

Obviously there is a long way to go from a laboratory experiment where we can watch cells migrate through some gel, and be able to turn this ability off, to the situation we might hope for in the future where this knowledge can be used to develop a treatment that prevents the cancer cells from spreading. Nevertheless it is a start. The work is exciting to watch unfold, and we have been extremely grateful to William’s Fund for all the support they have given us over the past years.

Chris Mitchell
Paediatric Oncologist
Oxford
1st May 2007

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