Genetics-complex diseases and cancer Flashcards
Remind and explain the 5 main mutation types
Silent-mutation in a codon that doesnt change the aa or the protein structure
Misssense-mutation in a codon that does change the aa or/and the protein structure
Nonsense-mutation that introduced a stop codon and truncates the protein
Addition, deletion-can be frameshifting (v bad)
What are the 10 hallmarks of cancer? Recall the 5 main ones in priority
4 main ones: Dysregulated growth (autologous growth pro signalling or insensitie to anti growth singalling), Evasion of apoptosis, limitless replicataion and genome instability (very important because can cause all the other ones)
On top of those: Sustained angiogenesis, Invasion/Metastatis, Dysregulation of energy metabolism, promotion of inflammation and evasion of immune system
Are all cancer cells in a tumour the same? Define driver mutations and their role, and what oncogenes and tumour suppressing genes are
Recall and explain Knudson two-hit hypothesis, and loss of heterogeneity
No, cancers are polyclonal-cumulative changes happen in different cancer cells, and tumours contain a wide variety of cells that have accumulated different mutations
Driver mutations are the main cancer causing genes-usually upregulation of oncogenes and downregulation of Tumour supressing genes are genes that down regulate cell division, check for DNA damage, induce apoptosism repair DNA. Oncogenes are genes that push replication, promoting growth and proliferation (usually activated by growth factors, TF, tyrosine kinases
Knudsons hypothesis is that both alleles of a tumor supressing gene have to be hit by a mutation to cause cancer (individual at risk, such as familial retinoblastoma, usually are born with one of those hits-greatly increase chance but never ‘certain”
For oncogenes-none are inheritly cancer causing (protooncogenes), but can override apoptosis (eg; BRAF in melanoma)
Loss of heterogeneity can occur by spot mutation (seen when DNA sequencing gives back different answers for a base), or by deletion of sections (DNA sequencing actually showns no difference then). Can also be non-sesnse, insertions or deletions
Describe genes involved in breast cancer predispositon, and the pathogenic mechanism of said gene
BRAC1 and 2 are both important predispotions to breast cancer (2-4% of BC)-60% risk of having it by age 90
BRAC are DNA repair genes for homologous recombination-mutated, DNA repair isnt as efficient and mutations accumulate faster
What are familial adenomatous polyposis and Lynch syndrome, what are they caused by and what is their relation with cancer
Use these exemples and BRAC exemple to explain patient management stratergy
FAP-mutations that cause greatly increased polyps in the colon-the whole colon is full of them-virtually 100% chance of cancer in a lifetime Lynch syndrome (HNPCC)-DNA mismatch detection genes-90% of familial cases-80% chance of colon cancer. can also be seen in many other cancers (ovary, upper GI, HpB, brain, skin) Manchester/amsterdam criteria help determine if there is a chance a person has inherited one of those genes, then DNA sequencing confirms it-from then, suveillancem prophylactic Sx, chemopreventio, etc
What is polygenic cancer? Explain polygenic, its link to cancer, to breast cancer, GWAS and transcriptome analysis
Polygenic cancer indicated that there is no one gene reponsible, but instead a plethora of small genes mutations that have small effect but are numerous
80% of breast cancer have no BRAC or distinguishable single mutation
GWAS was the idea of scanning many people with cancer to see which ones appeared more often-polygenic risk factors-SNP fishing
Another way to study polygenic cancer is transcriptome analysis-comparing gene expression in cancer cells to normal tissue-large patient cohors (microarray)-Found that serine proteases were upregulated in breast, prostate and ovarian cancers
So is it a cause? or a consequence? KLK14 gene was determined to be a small part of the cause
What are cytogenic changes is chromosomes? why do they matter to cancers?
Cytogenic changes are any visible changes of chr-structure or number (Aneuploidy, translocation, Macrodeletion/insertion)
Important in cancer because its so much DNA change it can be driver for many cancer
Translocation can cause fusion of proteins, as when the chr parts are stuck together, the transcript is linked-and they usually have abherrent function or regulation
quickly define leukemias vs lymhpomas
Lymphoid Leukemias-leukocytes T and B cells
Myeloid Leukemias-Macrophages, neutrophils
Can be acute (myeloid/lymphoblastic) or Chronic (myeloid or lymphocytic)
Lymphomas-RBC
Explain main features of chronic myeloid leukemia, philadelphia chromosome and the cause of the leukemia
CML-over production of mature granulocytes. 1,2 cases/100000, but 15% of adult leukemias. 3 phases-chronin (benign), accelaated, blast (actute-fatal)
Philadelphia Chr is in 90% of CML-t(9,22) which causes fusion of 2 protein-BCR-ABL (if no Chr-bad we cant treat it)
BCR-ABL makes a BCR-ABL Tyrosine kinase that is constantly active and signalling-
But because its only found in cancer-can be very specifically targetted-Imatinib blocks ATP binding site-aburdly good sucess rate-best drug available (small risk of relapse)-but can start being resistant
Monitor constantly with RT-qPCR-if responsive to treatment in 3-12 month, good. if not, change therapy
Explain main features of acute myeloid leukemia, APML and the cause of the leukemia
list 2 other cancer caused by fusion genes
AML is divided in FABMo7-medical emergency, FABM5-gum infiltration, less urgent
APML/AML3, or acute pronyelocytic leukemia, causes abnormal accumulation of immature granulocytes-
Causes by a fusion genes on a roberstosian transcolation (t15,17) (q22;q12) of the RAR alpha gene PML gene
RAR alpha is a transcription factor regulator of transcription
PML-RARa binds DNA too strong-blocks transcription of differentiation of granulocytes
Retinoic acid therapy helps dissociate co-repressors, but it doesnt kill cells-need continuous therapy forever after
Monitored by cytogenetics, FISH, or RT-qPCR
Burkitts lymphomas (cMyc-IgH) and Ewings sacroma (FL11-EWS)
What is pharmacogenetics and its relation to cancer? give a few exemples
Pharmacogenetics is the branch that deals with influence of genetic variation of drug response
In cancer-some cancers react differently. need to adaept treatment (chemotherapy)
Identify those likely to be affected, and those not (dont waste time, give something else)
Has determined a few: KRAS and cetuximad for colon cancer (reduce reaction), EGFR and getinib for lung cancer (increase chance) and BCR-ABL1-dasatinib for CML (unlikely to respond)
