Introduction

The androgen receptor A nuclear steroid receptor transcription factor activated by androgens like testosterone. plays a central role in prostate cancer..

Germ Cell Mutations

We already know such mutations cause hereditary diseases like Color Blindness, Haemophilia, and even some cancers (e.g. inherited BRCA1-deficient cells struggle to repair DNA and aid ER- breast cancers).

Somatic Cell Mutations

If downstream functional (effector) genes in a somatic cell are modified, it usually results in non-inheritable somatic cell mutation-based diseases (usually rare diseases), such as McCune-Albright Syndrome, Proteus Syndrome, etc.

However if upstream regulator genes (which suppress/activate cell division) are modified, it results in cancer (uncontrolled cell divisions). These regulator genes can be either Tumor Suppressors (LOF) or Oncogenes (GOF). LOF and GOF often work together to cause cancer.

There are 2 ways LOF and GOF happen :

1. Mutations
2. Copy Number Variations (CNVs) : deletion/amplification of chunks of genes

CNVs are generally more prevalent and disastrous. However it varies from gene to gene. For e.g., HER2 in breast cancer is more prone to amplification (CNV), while KRAS is activated by a mutation.

In high level regulator genes like TP53, its a mix : point mutations often act as the “first hit”, while CNVs frequently act as the “second hit” or later events that accelerate tumor growth.

To illustrate how common CNVs are in cancers, an average tumor sample consists of approximately 17% genome amplification and 16% deletion, compared to less than 0.35% and 0.1%, respectively, in normal samples

LOF

If TSGs or regulators that control TSGs like TP53, RB1, BRCA1, BRCA2, APC, PTEN, etc., are LOF-mutated, the brakes on controlled cell division are lifted.

Knudson’s 2-hit hypothesis posits that most tumor suppressor genes (TSGs) are recessive at the cellular level. This means you typically need to lose the function of both copies (alleles) of the gene to trigger cancer:

• First Hit: One copy is mutated/methylated (often inherited in hereditary cancers). This is called LOF (Loss of Function). The gene is still heterozygous.

• Second Hit: The second healthy copy is lost later in life. This is called LOH (Loss of Heterozygosity). The most common cause is the deletion of an entire chunk of a chromosome arm. This not only deletes concerned TSG, but also a bunch of bystander genes which are typically “housekeeping” genes necessary for cell survival.

GOF

Here genes like HER2, KRAS, BRAF, PIK3CA, MYC undergo amplification and drive cell growth pathways uncontrollably.

Albert et. al’s book “Molecular Biology of the Cell” has a chapter on Cancer which starts by defining cancer as a microevolutionary process. It says that unlike free-living cells such as bacteria, which compete to survive, the somatic cells of a multicellular organism are committed to altruistic collaboration for the sake of the organism and the germ cells. So any mutation that gives rise to selfish behavior by individual members of the cooperative will jeopardize the future of the whole enterprise. So if you start seeing mutation, competition, and natural selection operating within the population of somatic cells, cancer is begun !!

Cancer cells and their progenies start reproducing in defiance of the normal restraints. This gives rise to give rise to a tumor, or neoplasm- a relentlessly growing mass of abnormal cells. As long as the neoplastic cells remain clustered together in a single mass, however, the tumor is said to be benign, and a complete cure can usually be achieved by removing the mass surgically. A tumor is counted as a cancer only if it is malignant, that is, only if its cells have the ability to invade surrounding tissue.

Cancers are classified according to the tissue and cell type from which they arise. Cancers arising from epithelial cells are termed carcinomas (~90% of all human cancers) ; those arising from connective tissue or muscle cells are termed sarcomas. Cancers that do not fit in either of these two broad categories include the various leukemias, derived from hemopoietic cells, and cancers derived from cells of the nervous system.