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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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