Let’s talk about the basics of ALK Genetics. Imagine you are back in high school and your science teacher is going over a biology lesson.

Everyone is made up of cells, LOTS of cells. Inside the cells, there is DNA that is coiled into a superstructure called chromosomes. Scientists estimate we have about 30,000 genes in each cell. DNA is composed by nucleotides. Each nucleotide consists of three components:

a nitrogenous base: cytosine (C), guanine (G), adenine (A) or thymine (T)
a five-carbon sugar molecule (deoxyribose in the case of DNA)
a phosphate molecule

The backbone of the polynucleotide is a chain of sugar and phosphate molecules. Each of the sugar groups in this sugar-phosphate backbone is linked to one of the four nitrogenous bases. Each nucleotide has its preferred base pairs (A-T, G-C).

DNA is read by various protein complexes to translate the DNA code into proteins by transcription and translation.

In transcription, mRNA is made from the DNA. The result is a shorter script of DNA’s instruction, and the mRNA is carried to the translation machinery (Ribosomes). At the ribosomes, tRNAs come and bring in the amino acids to make a protein. This is a basic chart on “how to make a protein”. Every three nucleotides is a codon. Each tRNA will try to match a codon according to the chart. If it is a STOP, there is no more amino acid and the protein is completed. Modifications and protein folding are performed by another set of proteins to ensure the resulting protein will function correctly. If there are any mistakes at this point, there will be check points to throw away any aberrant products.

For ALK translocation, the gene for ALK is cut abruptly and is fused to a partner gene at the DNA level. Most often for us is the ELM4-ALK, but there are plenty of other partners too.

Since this happens in our cells, can I pass this disease to my children?

No, not really. Our ALK+ change usually occurs in your lungs and is not in your gonads for it to be pass down to your progeny. In order for you to pass it to your children, this change must have occurred in your sperm or egg.

Then why did I hear about a “family history” of cancer?

Each mutation can arise due to various reasons such as sunlight (ultraviolet-rays), chemicals such as tobacco, viruses, or just aging. There are many genes that can have mutations that can lead to no symptom. Most of the time, these aberrant cells are destroyed. Or the change really does not affect our cells; these are called silent mutations. However, when these changes occur in a critical gene in the gonads, then you can have a germline mutation that can pass down to your progeny. However, not everyone who inherited a genetic change, even like TP53, will get cancer. This is one of many “hits” a cell must have taken before carcinogenesis. Nature in 1958 already published the theory of “Multiple-mutation Theory of Carcinogenes” by J.C Fisher.

Over the years, we have found some genetic changes can result in cancer:

Tumor suppressor genes: These genes normally protect genes and limit cell growth.

These genes monitor how quickly cells divide into new cells.

Some of these genes repair those silent mutations (mismatched DNA pairing).

These genes control when a cell is destined to die.

Some names you must have seen before: BRCA1, BRCA2, p53 falls into this class of tumor suppressor genes.

Oncogenes: These are usually not germline changes. Changes in these genes actively turn healthy cells into cancer cells.

Genes that control cell growth.

Genes that turn off cell death.

Genes that control inter-cellular communication to organize cell growth and/or cell death together.

Some genes are: HER2, RAS family

DNA repair genes: These genes fix any mistakes that can occur when a cell replicates. If these genes are faulty, many mutations can accumulate in one single cell. Most of the tumor suppressor genes are actually DNA repair genes (BRCA1, BRCA2, and p53).

References:

https://pubmed.ncbi.nlm.nih.gov/19667264/

https://pubmed.ncbi.nlm.nih.gov/19667260/

https://www.cancer.net/navigating-cancer-care/cancer-basics/genetics/genetics-cancer

https://www.genome.gov/genetics-glossary/Mutation

https://www.nature.com/scitable/definition/silent-mutation-10/

https://www2.le.ac.uk/projects/vgec/highereducation/topics/dna-genes-chromosomes

https://www.cancer.gov/about-cancer/causes-prevention/genetics

https://www.nature.com/articles/181651b0

Author: Alice Chou

ALK Genetics 101