Molecular pathology part 1 Flashcards
Tumour diagnosis relies centrally on careful ……………… examination, supplemented by the judicious use of ………………….
The information gleaned by these means remains, without doubt, the single most important initial determinant of a patient’s ………….. and likely response to treatment.
However, in recent years the importance of mo………… assessment, as an adjunct to this examination has grown dramatically.
Tumour diagnosis relies centrally on careful morphological examination, supplemented by the judicious use of immunohistochemistry.
The information gleaned by these means remains, without doubt, the single most important initial determinant of a patient’s prognosis and likely response to treatment.
However, in recent years the importance of molecular assessment, as an adjunct to this examination has grown dramatically.
This has largely been driven by the emergence of new ‘targeted’ therapies where certain ………….. markers identify ………….. of tumours which may or may not respond to specific ………treatments (Zeron-Medina etal., 2015).
Testing for these markers is now mandatory prior to any decision on the type of novel treatment. It has also been shown that a range of molecular ……….. can contribute useful information for the diagnosis and ………… of particular tumours.
The evolving field of molecular pathology has produced a great deal of excitement by targeting particular therapies to specific tumours, offering two related sources of hope.
This has largely been driven by the emergence of new ‘targeted’ therapies where certain molecular markers identify subgroups of tumours which may or may not respond to specific drug treatments (Zeron-Medina etal., 2015).
Testing for these markers is now mandatory prior to any decision on the type of novel treatment. It has also been shown that a range of molecular markers can contribute useful information for the diagnosis and prognosis of particular tumours.
The evolving field of molecular pathology has produced a great deal of excitement by targeting particular therapies to specific tumours, offering two related sources of hope.
patients may be provided with more effective treatments improving their quality of life
Secondly, ineffective treatments with their concomitant side-effects may not be administered to patients in vain.
patients may be provided with more effective treatments improving their quality of life
Secondly, ineffective treatments with their concomitant side-effects may not be administered to patients in vain.
what is cancer
Boveri (1902): a disease of …………… chromosomes.
Diseases mostly driven by s………… mutations in DNA that occur during an individual’s lifetime.
Boveri (1902): a disease of scrambled chromosomes.
Diseases mostly driven by somatic mutations in DNA that occur during an individual’s lifetime.
somatic mutations in DNA - susceptibility to cancer
errors in DNA re………….
En…………… ex,,,,,,,,,,,,,,,,,,
range from …………… nucleotide mutations to l…………… chro……………. rea……………..
somatic mutations in DNA - susceptibility to cancer
errors in DNA replication
Environmental exposures
range from single nucleotide mutations to large chromosomal rearrangements
Germline vs somatic mutations
germline mutation in parental ………….. > embryo > ………… organism carries mutation > h………. of offspring gametes carry mutation
Somatic mutations
Parental gametes > e……… has s…………. mutation > mutation only in affected areas > ………. of gametes carry mutation
Germline mutations are in…………. and found in all cells
somatic mutations are not inherited and are found within the ……………..
Germline vs somatic mutations
germline mutation in parental gametes > embryo > entire organism carries mutation > half of offspring gametes carry mutation
Somatic mutations
Parental gametes > embryo has somatic mutation > mutation only in affected areas > none of gametes carry mutation
Germline mutations are inherited and found in all cells
somatic mutations are not inherited and are found within the tumour
Somatic mutations in cancer
…………. cell > ………. mutation > uncontrolled p…………….
TIME
Normal cell > Tumour population 1 tumour > population 2 tumour > population 3 tumour > Clonal mutation ( exist in ……… cancer cell pop 1)
>subclonal mutations ( exist in s……….. of cancer cells pop 1 and 2 )
Normal cell > DNA mutation > uncontrolled proliferation
TIME
Normal cell > Tumour population 1 > tumour population 2 > tumour population 3 > Clonal mutaion ( exist in all cancer cell pop 1)
>subclonal mutations ( exist in subset of cancer cells pop 1 and 2 )
Molecular pathology
Many conditions have characteristic, specific …………… changes, which when detected are diagnostic of that particular disease.
Inherited diseases and cancers.
A broadest definition of molecular pathology is the study of m………….. in a d………… state.
Molecular pathology techniques therefore, is to think of them in terms of the structure of the …………. and its rel………….. to g…….. expression.
Individual genes are located on ch………… and their transcription gives rise to R…, whose trans………… leads to p…………. expression.
Molecular pathology
Many conditions have characteristic, specific molecular changes, which when detected are diagnostic of that particular disease.
Inherited diseases and cancers.
A broadest definition of molecular pathology is the study of molecules in a disease state.
Molecular pathology techniques therefore, is to think of them in terms of the structure of the gene and its relationship to gene expression.
Individual genes are located on chromosomes and their transcription gives rise to RNA, whose translation leads to protein expression.
Molecular Pathology
Molecules studied are …., ….. and/or pro…….
Presence or absence of protein or RNA, or for an in………….. or ……………. in the amount of these molecules.
Rearrangements of large portions of ……..
Specific changes to the c………….. of genes.
Molecular Pathology
Molecules studied are DNA, RNA and/or protein.
Presence or absence of protein or RNA, or for an increase or decrease in the amount of these molecules.
Rearrangements of large portions of DNA.
Specific changes to the composition of genes.
Tests can then be divided into those which examine.
Mutations in individual …………, the poly……………. chain reaction (PCR).
Abno………….. of overall chromosome structure, pre……………. fluore………… in situ hybri………….. (FISH).
RNA abn……………/overex…………/viral activity/fusion partners, in situ hybrid…………… (ISH).
Ch……….. in pr……………expression, ……………………….(IHC).
Mutations in individual genes, the polymerase chain reaction (PCR).
Abnormalities of overall chromosome structure, predominantly fluorescence in situ hybridization (FISH).
RNA abnormalities/overexpression/viral activity/fusion partners, in situ hybridization (ISH). #Changes in protein expression, immunohistochemistry (IHC).
Two molecular techniques which do not fit into the main categories. are:Su…………. markers for alterations. An example, is A……… translocation testing where the presence of a t…………… can be examined directly using ………, but it is now more common to use I………. to examine for sec…………. ALK protein expression abnormalities. In some circumstances, it can be difficult or impractical to examine these factors directly and in some of these cases, where va………….. tests exist and clinical requirements are satisfied, it is common to use more easily assessable surrogate markers for alterations. An example, is ALK tra…………… testing where the presence of a trans………… can be examined directly using FI…….., but it is now more common to use IHC to examine for secondary ALK protein expression abnormalities.
Multiplex testing. One example is next-generation sequencing, a highly s…………… method of examining for multiple genetic ……………
Multiplex testing modalities allow multiple m……………… targets to be assessed in a single specimen, a situation which is becoming increasingly common as the number of acti…………., molecular alterations increases. One example is next-g……………… sequencing, a highly sensitive method of examining for multiple ……………. alterations
Two molecular techniques which do not fit into the main categories. are:Surrogate markers for alterations. An example, is ALK translocation testing where the presence of a translocation can be examined directly using FISH, but it is now more common to use IHC to examine for secondary ALK protein expression abnormalities. In some circumstances, it can be difficult or impractical to examine these factors directly and in some of these cases, where validated tests exist and clinical requirements are satisfied, it is common to use more easily assessable surrogate markers for alterations. An example, is ALK translocation testing where the presence of a translocation can be examined directly using FISH, but it is now more common to use IHC to examine for secondary ALK protein expression abnormalities.
Multiplex testing. One example is next-generation sequencing, a highly sensitive method of examining for multiple genetic alterations
Multiplex testing modalities allow multiple molecular targets to be assessed in a single specimen, a situation which is becoming increasingly common as the number of actionable, molecular alterations increases. One example is next-generation sequencing, a highly sensitive method of examining for multiple genetic alterations
