Notes

technologies that could dissect complex clonal architecture of cancers:
multiregion sequencing
single cell sequencing
analysis of autopsy samples
liquid biopsy samples

non small cell lung cancer :
genotype guided therapies
despite dramatic initial responses , all cancers develop resistance to targeted therapies. cancer as dynamic

driving forces behind intratumoral heterogeneity

Causes of intra tumoral heterogeneity
genomic instability
single base subst to whole genome doublings
exogenous mutagens:UV and smoke
errors in endogenous processes. , eg. microsatellite instability due to deficiency in DNA mismatch repair. increases somatic mutation burden
smoking related lung cancers have c->a transversion
mmr : c->t transition

an example of an endogenous process exploited by cancer cells to increase the frequency of mutations:

dC to dU -editing enzyme APOBEC3B
APOBEC3B mutational signature ( C to T and C to G) found in half of human cancers.

second driving force: the clonal evolution/ selection hypothesis

GI causes copy number imbalances,dynamic chromosomal instability

Peter Nowell model 1976
Tumor inititiation begins in a stochastic manner.
A nonmalignant cell is being induced a sleective growth advantage that leads to neoplastic proliferation.
gi of teh inc tumor gives the genetic diversity , subjected to evolutionary pressures
sequential emergence of genetically abnormal and heterogenous subpopulations.
linear evolution : successive acquisition of mutations taht gives selection advantage with the sequenctial clonesharburing the advantages outcompting the ancesral ones.

Branched evolution:
emergence and divergent propagation multiple subclonal tumor cell population that result from a common ancestor.

Solid tumors: mostly branced pattern while haematological malignancies :linear


The spectrum of tumor heterogeneity:
spatial :
cancer: ignore growth suppression signals, invade local tissues, metastasize to distant organs.
distinct molecular makeup of cancer cell from differebnt sites: different microenvironment.