Cancer, Genomic Instability, Genetic factors and Epigenetic factors

Cancer is a group of diseases which involves polymorphisms and/or alterations in the expression of genes that confer undiminished proliferative and survival advantage to somatic or germinal cells.

Genomic Instability:

Clear distinction between cancerous and non-cancerous cell proliferation lies in genomic instability. Cancer cells contain multiple genetic and epigenetic alterations. As cancers progress, the numbers of alterations in their genome tend to increase. Cancers, even if outwardly homogeneous, usually consists of cell clones that differ at least slightly in their genetic constitution.

                                  The variant clones are continuously selected for those proliferating fastest, tolerating adverse conditions best, capable of evading immune responses etc.., with the best- adapted cell clone dominating growth

                                     Cancers with genomic instability will display greater variation and a higher risk of developing resistance.

Epigenetic factors: Methylation changes occur early and ubiquitously in cancer (Feinberg*., 2016)

     

Table.1 Hypomethylation and hypermethylation in cancer

	Hypomethylation	Hypermethylation
Frequency	Ubiquitous even in the earliest benign tumors	Some early hypermethylation, with increasing frequency with tumor progression
Targets	Repetitive sequences, coding regions, promoters	Promoters
Primary/ secondary change	Primary?	Can be secondary to gene silencing, chromatin changes
Possible effects in humans	Chromosomal instability, loss of imprinting, oncogene activation	Maintenance of tumor-suppressor-gene silencing
Effects in animal models	Lymphoma, Increased intestinal tumor initiation, Liver cancer	Increased intestinal tumor progression
Variation in the age of onset	Yes	Yes
Therapy	Inhibitor side effect?	Inhibition therapy

Genetic factors:

 Three main classes of genes:

a. (Proto) Oncogenes

b. Tumor Suppressor Genes and

c. DNA repair genes contribute to the development of cancer genotype and phenotype. These genes resist the natural and inherent death mechanism(s) embedded in cells (apoptosis and like processes), coupled with dysregulation of cell proliferation events.

Table.6: Genes which contribute to Cancer (Vogelstein et al., 2014)

Gene	Major heredity tumor types
Tumor –suppressor genes	Colon, thyroid, stomach, intestine
APC	Colon
CDH1 (E-cadherin)	Stomach
EXT1,2	Bone
TP53 (p53)	Breast, sarcoma, adrenal, brain
Stability genes
MUTYH	Colon
BRCA1, BRCA2	Breast, ovary
MSH2, MLH1, MSH6,PMS2	Colon, uterus
XPA, C; ERCC2-5; DDB2	Skin
Oncogenes
KIT	Gastrointestinal stromal tumors
MET	Kidney
PDGFRA	Gastrointestinal stromal tumors
RET	Thyroid, parathyroid, adrenal
15-LOX-1	Prostate, colorectal, breast
15-LOX-2	Prostate, colorectal
12-LOX	Breast, Ovarian, Colon
5-LOX	Breast, Ovarian, Colorectal

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