bimm paper Flashcards
When analyzing cancer genomes, what are the characteristics of “mountains” vs “hills”
use the description listed in the abstract
Mountains: genes altered in a high percentage of tumors
Hills: genes altered infrequently
What is the most common class of cancer mutations observed and what effect is usually observed on the
resulting protein sequence?
“an average of 33 to 66 genes display subtle somatic mutations that would be expected to alter their protein products, 95% of these mutations are single-base substitutions”
“90.7% result in missense changes, 7.6% in nonsense changes, 1.7% in alterations in splice sites
What is the average # of mutations in a given cancer? Which cancers have much higher # of mutations?
Why?
Melanomas (skin cancer) and lung tumors contain ~200 nonsynonymous mutations per tumor, which is reflected if the involvement of potent mutagens (ultraviolet light, cigarette smoke)
What is the basic distinction between “driver” mutations vs “passenger mutations”?
Driver: mutations that confer a selective growth advantage to the tumor cell, small selective growth (0.4%)
Passenger mutations: all pre-neoplastic mutations, have no effect on the neoplastic process (the accumulation of somatic mutations in certain genes that thus give rise to tumor cells, with consequent assignment of function to those genes involved)
What are “gatekeeper” gene/mutations? How does this relate to colon cancer progression?
Describe why colorectal tumors usually contain more mutations than brain and pancreatic tumors?
Leukemias?
Colorectal tumors contain more mutations than brain and pancreatic tumors becuase the epithelial cells lining the crypts of the colon replicate, whereas the glial cells of the brain and epithelial cells of the pancreatic ducts do not replicate
passenger mutations are the cause of this
Do the mutations seen in metastastic lesions differ greatly from the primary tumor? Explain.
The mutations seen in metastastic lesions are all present in a large number of cells in the primary tumors, this is because primary tumors are thought to develop into metastastic cells, and even if the primary tumor is removed, the metastastic cells are all present in the circulation and they enlarge
Although the genetic mutation that converts primary tumors to metastatic is still unknown
Explain why the “rates” of major genetic alterations (chromosomal translocations;gene amplifications) are
high while still representing a small number protein changes.
Explain how “driver genes” differ from “driver gene mutations”. Can drive genes cause passenger
mutations? Explain.
Driver genes contain driver gene mutations, and they may also contain passenger gene mutations
Driver genes are based on frequency of mutations in an individual gene compared with the mutation frequency of other genes in the same or related tumors
Returning to Q#1, are mountains usually considered driver or passenger mutations. What contributes to
the difficulty in analysis of the “hills”?
Mountains are usually considered driver gene, as the have a number of muatations in TP53 or KRAS
The difficulty in analysis of the hills is that because they dominate cancer genome landscapes and the background rates vary so much among different patients and regions of the genome
What is a mut-driver gene vs epi-driver gene?
Mut driver gene: contain a sufficient number or type of driver gene mutations to unambiguously distinguish them from other genes, classified by their pattern of mutation rather than their mutation frequency
Epi driver gene: expressed aberrantly in tumors but not frequently mutated; they are altered through changes in DNA methylation or chromatin modification that persist as the tumor cell divides
what are oncogenes and tumor suppressors in mut drivers
Oncogenes are recurrently mutated at the same amino acid positions, whereas tumor suppressor genes are mutated through protein truncating alterations throughout their length
Explain how the 20/20 rule can classify mut drivers as oncogenes or tumor suppressors
oncogenes: >20% of the recorded mutations in the gene are at recurrent positions and are missense
tumor suppressors: >20% of the recorded mutations in the gene are inactivating
Approximately, how many mut-driver genes have been identified? What are about ½ of these genes and
what is the significance of this (Note: this can be confusing…do not confuse this subclass of mut-driver genes
with epi-driver gene)?
125 mut driver genes
71 are tumor suppressor genes
54 are oncogenes
Tumors with what kind of alterations result in higher numbers of mutations?
mutations in proofreading domains, DNA polymerases: POLE, POLDI
and
tumors with mismatch repair defects can harbor thousands of mutations more than lung tumors or melanomas
