Genetics 10 - Cancer & Genomic Medicine Flashcards
Nature of most cases of cancer
Sporadic
< 10% of all tumours result from a familial disposition
Still a GENETIC disease
Cancer
General term for all malignant neoplasms
Malignant
when it grows independently of control mechanisms, being capable of transcending tissue boundaries, growing invasively, and metastasizing
Basal cell carcinoma
Very low metastatic potential and may grow and filtrate surrounding tissue without metastasizing for many years
Carcinomas
develop from epithelial tissue (e.g., skin, intestinal epithelium, bronchial epithelium, and the epithelium of the glandular ducts such as the mammary glands or pancreas)
Sarcomas
originate from mesenchymal tissue (e.g., connective tissue, bones, muscles)
Leukaemias and lymphomas
malignant diseases of the haematological and lymphatic systems
How do most cancers develop
Through progressive accumulation of various mutations within a cell
These genetic changes are typically acquired somatically, although some can be transmitted through the germ line and are present at birth in every body cell
Protooncogenes
Genes that, through (dominant) activating mutations, can be turned into oncogenes
Oncogenes facilitate malignant transformation by synthesis of structurally altered or defective proteins
Tumour suppressor genes
Genes that are relevant for the regulation of growth, repair, and cell survival, with malignant transformation supported through (recessive) loss-of-function mutations on both copies of the gene
They typically include DNA repair genes that are responsible for detecting and repairing genetic damage within a cell
Malignant transformation
The change from controlled to uncontrolled growth of a cell that is caused by mutations in oncogenes or tumour suppressor genes
Cancer is the result of
accumulation of several genetic and chromosomal changes
Tumour progression model - adenoma carcinoma sequence
Explains impact of a succession of different gene defects on tumour development
(normal tissue → adenoma → carcinoma in colon takes 10 years)
uncontrolled growth of a tumour
disruptions in intracellular, as well as intercellular, processing of information
Cell proliferation and cancer?
Not from cell proliferation
Question of balance between cell division and growth on 1 side
and apoptosis on the other
Differentiation of a malignant tumour
A malignant tumour tends to be less differentiated than its tissue of origin
How do oncogenes develop
from protooncogenes through hypermorphic mutations that result in gain of function
mutations are mostly missense - cause permanent activation or altered function of the gene product (qualitative changes)
Translocations and protooncogene
translocations can turn a protooncogene into an oncogene by generating a fusion gene with novel function and/or placing it under the control of a new, constitutively active promoter, which might trigger abnormal expression with regard to organ system or developmental stage
2nd way in which protooncogenes can be multiplied
Amplification
Increased gene copy numbers and thus more gene products in cell - quantitative
Intracellular dominance of oncogenes
Oncogenes are dominant at the cellular level, which means that activation or overexpression of one single allele is sufficient to result in a change of the cell’s phenotype
What are typical protooncogenes involved in
pathways that regulate cellular growth, cell proliferation, and the cell cycle
receptor tyrosine kinases
growth factors and their receptors
components of intracellular signaling cascades
proteins that regulate the cell cycle
RAS genes code for
guanosine triphosphate (GTP) binding proteins that have a crucial regulating function for several important signaling cascades in the cell
K-RAS mutations
90% of all pancreatic carcinomas
50% of all colon cancers
N-RAS
30% of all AML - Acute Myeloid Leukaemia
HER2/neu
Receptor tyrosine kinase
Important protooncogene in breast cancer
Philadelphia chromosome, t(9;22)q(34;11)
example of a chromosomal translocation resulting in activation of a protooncogene is the translocation between chromosomes 9 and 22
translocation causes a fusion of the BCR and ABL genes, leading to a fusion protein, BCR-ABL, and constitutional activation of the ABL tyrosine kinase
promoters for genes of the immunoglobulin chains
chromosome 14, 22 and 2
Result of translocation of protooncogenes into chromosomal regions that are under the control of promoters for genes of the immunoglobulin chains
uncontrolled, constitutive expression
MYC protooncogene
Burkitt lymphoma
Chromosomal translocations as causes of malignant diseases
Prognostic importance of tumour-specific balanced chromosome translocations
They are found only in tumor cells and thus represent somatic mutations
A cytogenetic analysis of the abnormal cell line should be included in the standard workup of most leukemias and lymphomas and may supply information on treatment strategies
Most common cytogenic change in paediatric Acute Lymphoblastic Leukemia
t(12;21)(p13;q22) translocation, which generates a TEL-AML1 fusion gene
BCR-ABL fusion gene and age
it is present in 5% of children, 35% of adults, and more than 50% of individuals over 60 years of age with ALL
particularly malignant form of the disease
median survival time of < 9 months when treated with conventional ALL regimens because of high early relapse rate
Most familial cancer predisposition syndromes result from
mutations in tumour suppressor genes in which loss of function favors development of a tumour
Products of TSGs
inhibit cellular growth, proliferation, or cell cycle progression (gatekeeper genes)
ensure genetic stability, for example, through DNA repair (caretaker genes)
How are oncogenes activated
Mutations on a single allele
How is a tumour-promoting phenotype associated with tumour suppressor genes is triggered
Inactivating mutations in BOTH ALLELES
these mutations are therefore recessive on a cellular level
Frequent TSG mutations
null mutations that cause complete absence of a functional product, such as small frameshift deletions or nonsense mutations that cause aborted protein synthesis
Unclassified variants
Missense mutations
Variant of unknown significance
A genetic variant identified in a patient with a particular disease or a suspected disease predisposition that may or may not be of functional importance
2-hit hypothesis of cancer development
Cancer development involves two successive mutations that affect the two alleles of a tumour suppressor gene
In familial cancer disposition syndromes, a mutation on one allele is inherited, and only one additional hit is required for cancer development
Sporadic retinoblastoma
did not inherit a mutation and require two independent somatic mutations affecting the same cell
2 hits required
congenital - one of the mutations is already present - a somatic mutation is likely to occur in at least one relevant cell, the disease occurs almost inevitably and much earlier in constitutional mutation carriers than in noncarriers - Frequently, secondary tumours can develop independently (e.g., osteosarcoma and leukemia)
What is seen in constitutional tumour predisposition syndromes, one mutated allele derives from the parental germ line so that offspring will have only one wild-type allele in all of their body cells (first hit)
1 mutated allele derives from the parental germ line so that offspring will have only one wild-type allele in all of their body cells (first hit)
Each additional inactivating mutation of the second (wild-type) allele causes loss of function of the respective gene product within the affected cell (second hit)
Recessive = dominant
Although inactivation of tumour suppressor genes reflects a recessive mechanism at the cellular level, the associated cancer predispositions are inherited as (autosomal) dominant disorders
Incomplete penetrance of an autosomal dominant tumour predisposition syndrome
Patients who never experienced a 2nd hit in the relevant organ in their lifetime
hence would not develop any tumour
Where is this paradox of a a dominant disorder with a recessive pathomechanism at the cellular level apply to
All conditions where abnormal functioning of a single cell is sufficient for the development of clinical symptoms
Necessity for modification of 2-hit hypothesis
2nd hit in 2nd allele did not necessarily have to involve a DNA change
Epigenetic processes, such as DNA hypermethylation, can also account for the inactivation of an allele of a tumour suppressor gene
Since the methylation status of a gene remains the same throughout all mitotic cell divisions, the effect resembles that of a true alteration of the DNA sequence
DNA repair genes
Inactivation of DNA repair genes does not immediately trigger abnormal cellular growth or differentiation
However, it causes failure to identify and repair mutations in the entire genome => increase in mutation rate
Has an impact on protooncogenes as well as other tumour suppressor genes/gatekeeper genes
accumulation of mutations is a decisive factor in tumour progression, inactivation of DNA repair genes significantly accelerates malignant transformation
Lynch Syndrome
Hereditary tumour predisposition caused by mutations of DNA repair genes
Due to mutations in DNA mismatch repair genes e.g. MSH2 or MLH1
How do lesions associated with FAP develop
These lesions follow the adenoma–carcinoma sequence, starting as benign epithelial tumors and developing over a period of years into epithelial dysplasia and finally to colorectal carcinoma
Lifetime disease risk associated with Pathogenic Mutations in BRCA1 and BRCA2
NCCP criteria for diagnostic BRCA1/2 testing
