Carcinogenesis is
considered to be the result of many environmental factors such as chemicals,
radiation and UV-B. However, research has shown that these factors can rarely
provoke a change in the genes and finally cause cancer, simply because the
cells have mechanisms that enable them to detect and repair the cell damage
that has been done [1].Base excision repair (BER) and nucleotide
excision repair (NER), are responsible for removing and eliminating either
small lesions in the basis or UV DNA damages or prompting the apoptosis if it
is necessary [2]. On the other hand, hereditary gene mutations
appear to cause cancer at a much higher rate [1]. Mismatch repair
(MMR), is also a repair DNA mechanism, restoring mistakes in basis, such as
mismatching and wrong insertions or deletions during DNA replication. A
possible mutation in a DNA repair mechanism can affect the oncogenes and
trigger uncontrolled cell growth [1]. Additionally, chromosomal
abnormalities such as structural abnormalities and numerical abnormalities, are
also at fault for carcinogenesis. In B-Acute lymphoblastic leukemia, 41% of the
patients have numerical chromosomal abnormalities while the 35%, have
structural abnormalities [3]. Chromosomal abnormalities can be
caused by mitosis or meiosis during the embryonic state, and some of them can
be inherited [4]. This paper aims to discuss cancer cases caused by
genetic mutations that possibly were created during the embryonic state either
by a spontaneous mutation or hereditary.
One syndrome
caused by hereditary mutations in DNA repair genes, is the Lynch syndrome, the
hereditary colorectal cancer not associated with polyposis. [5].
Patients appear to have adenomas and tumors mostly on the right side of their
colon [6], on the cecum [5]. Tumors can also be found on
the transverse colon [5], while the adenomas frequently turn to
tumors [6]. Mismatch repair
genes are responsible for fixing erroneous matching in the DNA basis. The basis
A-T is a normal matching while the basis G-T is not normal and MMR genes are in
charge of correcting the mistake [5]. Some of the MMR genes are
MLH1, MSH2, MSH6, and PMS2 and either of them can undergo a germline mutation.
A patient with Lunch syndrome has one mutated MMR gene and this results in
leaving some erroneous basis without correcting them which will end up in a
dysfunctional copy [6]. Some cases of germline deletions in the 3’
end of the EPCAM molecule also seem to cause Lynch syndrome [7]. The
MMR genes are inherited with an autosomal dominant manner and the patients have
a higher risk of developing other type of cancers such as gastric, ovarian,
glioblastoma, urothelial, sebaceous gland adenomas, and keratoacanthomas[6].
BRCA1 gene
normally, encodes a phosphoprotein responsible for stabilizing the genome and
regulating the cell division and replication. BRCA1 protein forms bonds with
other proteins that recognize DNA damages in the structure or in the DNA
replication, with signal transducers and tumor suppressors, forming a bigger
molecule unit called the BRCA1-associated genome surveillance. BASC interacts
with RNA polymerase II and with histone deacetylase complexes, having a vital
role in many DNA functions, and especially in DNA-repair [8]. BRCA2
is also a tumor suppressant gene, that encodes a protein which by its BRC
motif, binds to the RAD51 recombinase [9]. RAD51 is an ATPase
protein important for the homologous recombination of DNA during double strand
break repair, replication stress and meiosis. Typically, the protein invades
base-paired homologous DNA sequences, helping the correct DNA repair [10].
Inherited germline mutations in both BRCA1 and BRCA2 are the cause for the 50%
of female breast cancer cases while they are associated with ovary cancer in
women and prostate cancer in men. Mutations in BRCA2 have also been associated
with pancreatic cancer, melanoma, and B cells cancer [11]. Some of
the mutations that can occur include deletions, insertions, splice-site
mutations, rearrangements, missense mutations, and variants of unknown
significance. Deletions and insertions can insert a premature termination codon
[12] and possibly develop aneuploidy [11]. Splice-site
mutations and rearrangements can cause the addition or the loss of exons which
can alter the function of the gene. Variants of unknown significance can result
in a synonymous substitution [12]. Cancer can be developed only of a
patient has inherited a mutation in both of their BRCA1 variants, or in both of
their BRCA2 variants [11] .
RAG1 and RAG2
genes both have a vital role in the immune system [13]. Τhe genes
that are responsible for encoding the heavy and light chains of the antibodies,
undergo a rearranging process. This results in the production of
immunologically mature B cells. This process is called VDJ recombination, and
it creates a wide range of antibodies [14]. RAG1 and RAG2 proteins
are necessary for the recombination of the VDJ segments and bind with the
recombination signal sequence (RSS) [13]. Experiments that took
place on mice, showed that mice without the RAG1 gene, have not developed
matured B and T lymphocytes. While there are B and T cells, they do not mature
further [15]. In humans, mutations in the RAG gene such as deletions
and translocations, have been associated with the development of Leukemias [16]
[17], while the increase of RAG1 is found in B-ALL and in many
proliferation markers in ALL. In some cases, the RAG1 increase has been
associated with the deletion of IKZF1, however mutations in the RAG genes are
found in lymphoid malignancies [17]. Mutations in the RAG family can
be inherited [18].
People who have 50
chromosomes or more in their karyotype, suffer from a numerical abnormality
called hyperdiploidy. This condition is often caused either by the duplication
of one haploid line or by the addition of an extra chromosome in the diploid
line. Hyperdiploidy has been linked with B-Acute Lymphoblastic leukemia,
T-acute lymphoblastic leukemia, and multiple myeloma [19].
Specifically, the 25-30% of the children with B-ALL appear to have high
hyperdiploidy [20]. On the other hand, hypodiploidy, a karyotype
with less than 44 chromosomes, is much more unusual. It is often found in cases
of acute lymphoblastic leukemia and has a bad prognosis. Hypodiploidy has been
linked to the Ras and the IKZF3 genes, while other cases of Hypodiploidy have
been linked to the TP53, RB1 AND IKZF2 genes [19].
A translocation
between the 11th and the 21st chromosome, t(11;21) results in the fusion of the
genes ETV-6 and RUNx1 [19].
ETV-6 is a gene that encodes a transcription factor, ETV6, which controls the
growth of blood cells. The protein interacts with other proteins that control
the growth and the differentiation of cells [21]. It also restricts
FLI1, another transcription factor which enables the maturation of
megakaryocytes and obstructs the differentiation of erythroblasts into red
blood cells which can end up. It is observed how ETV6 protein plays a vital
role in restricting and inhibiting other proteins, and the absence of it, could
end up in a constant proliferation and abnormal structure of erythroblasts. RUNX1
gene encodes the RUNx1 protein, another transcription factor which regulates
the differentiation of hematopoietic stem cells. The protein is expressed in
places of the embryo such as the yolk sack and the aorta-gonad-mesonephros
where it helps the endothelial transition slowly into a hematopoietic cell.
Additionally, research has indicated that mice without the RUNx1 protein have
primitive erythrocytes with altered structure and their blasts appear smaller
in size. The fusion of those two genes (ΕTV6-RUNx1) results in the repression
of RUNX1’s transcription. This abnormality is present in the 20-25% cases of
B-ALL and while it is rarer it is still apparent in some patients with T-ALL
mostly commonly found in children[22] .
Much attention has
been drawn to another structural abnormality regarding the MLL gene. This gene
encodes a protein that regulates the transcription of specific genes and plays
a vital role in the normal hematopoiesis and differentiation. Some functions of
the protein consist of methylations, trimethylations, dimethylations and the
regulation of the epiblast stem cells [23]. The
MLL gene is located in the 11th chromosome (11q23). An abnormality such as
translocations can create genes fusions [19][24][25][26]
|
t(4;11)(q21;q23) |
MLL-AF4 |
|
t(6;11)(q27;q23) |
MLL-AFDN |
|
t(9;11)(p22;q23) |
MLL-AF9 |
|
t(2;11)(q37;q23) |
SEPT2 |
|
t(9;11;19)(p22;q23;q13.3) |
MLL-ENL |
|
t(11;17)(q23;q25) |
KMT2A::SEPT9 |
|
t(11;22)(q23;q11) |
KMT2A::SEPT5 |
|
t(10;11)(p12;q23) |
MLL-AF6 |
These
translocations are observed in ALL. Children less than 6 months old with B-ALL
have bad prognosis while older kids or adults with ALL can show a better prognosis
[19].
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