Review Question 1
If you were studying the mutations in an oncogene identified by sequencing in a large
number of tumors, what patterns of mutations would you expect to see?
To date, more than 280 genes with oncogenic activity have been described, some of
which are specific to a particular cancer type. Some notable ones include HER2 and ESR1
in breast cancer, BRAF and NRAS in melanoma, EGFR, ROS1, ALK, and RET in lung
cancer, KRAS, BRAF, and PIK3CA in lung and colorectal cancer, and KIT in acute myeloid
leukemia [4]. These genes are usually affected by missense mutations, which change a
single amino acid in the protein sequence, or by gene amplifications or transcriptional
overexpression. Also, typically mutations in these genes are acquired somatically, as (with
a few exceptions such as RET) germline activation of these may not be compatible with life.
2.2.2 Tumor Suppressors
Tumor suppressor genes are so named because when they become inactive through the
acquisition of somatic mutations, tumor growth is accelerated. As can be expected, their
functions typically involve cell cycle control, regulation of apoptosis, and DNA break
repair, among others. Since inactivating mutations were found in the first discovered tumor
suppressor gene, RB1, in 1986, more than 270 genes have been identified to contribute to
cancer development when they are inactivated in different cancer types [1].
Review Question 2
If you were studying the mutations in a tumor suppressor gene identified in a large
sequencing study, what patterns of mutations would you expect to see?
The most commonly mutated gene in human cancer, TP53, is a tumor suppressor, which
regulates transcription to control cell growth arrest and apoptosis, and, therefore, the
majority of cancer-derived missense mutations affect its DNA binding domain and usually
are associated with advanced stages of cancer [5]. Examples of other important genes in
this category are CDKN2A and NF1 in melanoma, BRCA1 and BRCA2 in breast cancer,
and ATM in certain leukemias [1, 4]. These genes are typically affected by stop-gain,
frameshift-inducing or splice site mutations, by deletions that can span a few amino acids
or the whole gene, or by gene silencing via transcriptional downregulation. Many of the
genes that are cancer-predisposing in individuals are tumor suppressors, with inactivation
of the remaining allele occurring later in life.
2.2.3 Gene Fusions
Gene fusions are another category of cancer-promoting genomic alterations that arise
through structural rearrangements that combine two genes in a novel transcript, usually
20
C. Molina-Aguilar et al.
If you were studying the mutations in an oncogene identified by sequencing in a large
number of tumors, what patterns of mutations would you expect to see?
To date, more than 280 genes with oncogenic activity have been described, some of
which are specific to a particular cancer type. Some notable ones include HER2 and ESR1
in breast cancer, BRAF and NRAS in melanoma, EGFR, ROS1, ALK, and RET in lung
cancer, KRAS, BRAF, and PIK3CA in lung and colorectal cancer, and KIT in acute myeloid
leukemia [4]. These genes are usually affected by missense mutations, which change a
single amino acid in the protein sequence, or by gene amplifications or transcriptional
overexpression. Also, typically mutations in these genes are acquired somatically, as (with
a few exceptions such as RET) germline activation of these may not be compatible with life.
2.2.2 Tumor Suppressors
Tumor suppressor genes are so named because when they become inactive through the
acquisition of somatic mutations, tumor growth is accelerated. As can be expected, their
functions typically involve cell cycle control, regulation of apoptosis, and DNA break
repair, among others. Since inactivating mutations were found in the first discovered tumor
suppressor gene, RB1, in 1986, more than 270 genes have been identified to contribute to
cancer development when they are inactivated in different cancer types [1].
Review Question 2
If you were studying the mutations in a tumor suppressor gene identified in a large
sequencing study, what patterns of mutations would you expect to see?
The most commonly mutated gene in human cancer, TP53, is a tumor suppressor, which
regulates transcription to control cell growth arrest and apoptosis, and, therefore, the
majority of cancer-derived missense mutations affect its DNA binding domain and usually
are associated with advanced stages of cancer [5]. Examples of other important genes in
this category are CDKN2A and NF1 in melanoma, BRCA1 and BRCA2 in breast cancer,
and ATM in certain leukemias [1, 4]. These genes are typically affected by stop-gain,
frameshift-inducing or splice site mutations, by deletions that can span a few amino acids
or the whole gene, or by gene silencing via transcriptional downregulation. Many of the
genes that are cancer-predisposing in individuals are tumor suppressors, with inactivation
of the remaining allele occurring later in life.
2.2.3 Gene Fusions
Gene fusions are another category of cancer-promoting genomic alterations that arise
through structural rearrangements that combine two genes in a novel transcript, usually
20
C. Molina-Aguilar et al.