The basis of cancer is genetic, using hepatitis B virus to illustrate the case

The main theme of this post is to say “the basis of cancer is genetic; the cancerous state is maintained by genes.”

The difference of germ cell mutation and somatic cell mutation  

Speaking of ‘genetic’, many automatically relate that it comes from parents and will pass along to children.  But, that is not the case.  There are two main types of cells: germ cells and somatic cells.  Germ cells are sex cells (gametes) that include sperms and eggs.  Each gamete contains one set of chromosomes (23).  When a boy (sperm) meets a girl (egg); they unite to form zygote (contains 2 sets of chromosomes or 46) which is the very beginning of an embryo.

Thus gamete (either sperm or egg) mutation can pass along to offspring, such as sickle cell anemia, cystic fibrosis or color blindness. Somatic (body) cells mutation will not pass along to offspring, but may cause cancer.

The basis of cancer is genetic                      

One needs to grasp two concepts to understand the story of why the basis of cancer is genetic:                              

(1)  Virus infection may lead to cancer; virus does it by ‘manipulating’ our genes.                                                 

(2)  Mutation of our genes (caused by virus or by chemical agents or radiation) leads to cancer.

Renato Dulbecco first demonstrated a viral infection may lead to cancer 

Dr. Renato Dulbecco

I wrote an obituary of Renato Dulbecco in February 2012 when he died, I called it “Remembrance (which is the obituary for Wall Street Journal): Renato Dulbecco”, to protest WSJ for not having a “Remembrance” for such a medical giant.

http://doctorjytsai.blogspot.com/2012/02/remembrance-renato-dulbecco-1914-2012.html

Dulbecco (at Caltech in 1960s) was the one demonstrated that DNA of a virus can integrate into the chromosomal DNA of the host cell, causing the uncontrolled cell growth, which is the genetic basis of cancer, and for which he was awarded a Nobel Prize in 1975, thus viral genes transform normal cells into cancer cells.

Michael Bishop and Harold Varmus (at UC Medical School at San Francisco in 1975) discovered the origin of so-called ‘cancer gene”, which is not of virus, but of our own gene.

Michael Bishop and Harold Varmus: The concept of proto-oncogene and oncogene 

Dr.Michael Bishop

If a given (human) gene is picked up and transduced/transformed by retrovirus (i.e. when cell is infected by retrovirus) into an oncogene, then this given human gene is called proto-oncogene.

In addition to virus being the culprit to transform a proto-oncogene to oncogene, certain chemical agents or radiation can cause a mutation of a proto-oncogene to become an oncogene, these chemical agents are called carcinogens, which are usually mutagens.

Michael Bishop and Harold Varmus worked on the Rous sarcoma virus (see the story later) in the early 1970s to make this discovery.  Even though the cancer is caused by virus, but the so-called ‘viral oncogenes’ are not truly viral at all but are of human genes in origin.  They discovered the retrovirus genomes are incorporated into the human gene and exploited to wreak havoc.  Michael Bishop and Harold Varmus were honored with Nobel Prizes in Medicine for this pivotal discovery in 1989.

Dr. Harold Varmus

The sequence of nucleotide in an oncogene can be different by only a single nucleotide from the sequence of the corresponding proto-oncogene, which is still normal and healthy.

Since the nucleotides sequence of a gene (DNA) is translated into the amino acid sequence of a protein the gene makes, so the sequence of amino acid of a oncogene protein [made by oncogene] can be different by only a single amino acid from the sequence of the corresponding proto-oncogene protein [made by proto-oncogene].

Dr. Peyton Rous

This is a good example that a single amino acid (among millions) goes astray can wreak havoc to cause cancer or sickle cell anemia.

Peyton Rous started it all 

Peyton Rous was honored with a Nobel Prize in Medicine in 1966, almost 40 years after he first discovered a virus (now bears his name) cause cancer in chicken.  This is the main reason why Michael Bishop and Harold Varmus picked Rous sarcoma virus to work.

A visit by Dr. Chih-Wen Lin whose article in the Journal of Hepatology prompted me to write this article article

Last week our friend, Dr. Chih-Wen Lin came to visit us from Taiwan.  有朋自遠方來，不亦樂乎。.  His article (“Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis”) in 2013 Journal of Hepatology (see photo) prompted my writing of this article.

Dr. Lin is the Director of the Department of Gastroenterology at E-DA Hospital/I-Shou University in Kao-Hsiung, Taiwan.  Their data showed that the 5-year cumulative incidence of hepatocellular carcinoma (HCC) is 10.7% in alcoholic cirrhotic patients, and the alcoholic cirrhotic patients with concomitant hepatitis B virus (HBV) infection have significantly higher incidence of HCC (36.8%) than those with HBV infection alone or alcoholism alone.

The focus of this post is not to discuss Dr. Lin’s article, but to show you that alcoholic cirrhosis without HBV infection can also lead to HCC (liver cancer).  In fact, cirrhosis from steatohepatitis (the most severe form of fatty liver), hemochromatosis or Wilson disease can also lead to HCC, less frequent though it may be.

The mechanisms of liver cancer-making in hepatitis B and hepatitis C are different                

Up to 90% of patients with hepatocellular carcinoma are known to have chronic liver disease and cirrhosis, hepatitis B infection may be a rare exception; HBV can cause HCC in the absence of cirrhosis, in contrast to HCV-related HCC which is found almost exclusively in patients with cirrhosis.

Hepatitis B virus (a DNA-containing virus) is able to integrate its DNA into the DNA of the host cells to transform it into oncogene, whereas hepatitis C virus (an RNA-containing virus) doesn’t have this ability.

The mechanism of how HCC (liver cancer) is formed is quite heterogeneous and complex, hepatitis B and hepatitis C play a big role, but they are not the sole perpetrators.  Alcohol is an important cofactor in patients with either hepatitis B or C infection with cirrhosis that leads to HCC (liver cancer), the mechanism of which is not clear, or at least unknown to me.  I read somewhere that telomerase is even involved.

Dr. Baruch Blumberg: A towering figure in medicine, a humble scientist and a great man           

It would be remiss of me not to mention Dr. Baruch Blumberg while talking about hepatitis B.  He discovered Australia antigen, later proved to be hepatitis B surface antigen (HBsAg), the origin of hepatitis B infection in mid-1960s, leading to the Nobel Prize in Medicine in 1976. His memoir is “The Hunt for a Killer virus: Hepatitis B”, a fascinating story.

He also made the first hepatitis B vaccine that was used in Taiwan.  His The Lancet article (Nov. 1, 1969) connected hepatitis B related cirrhosis to hepatocellular carcinoma (primary liver cancer).  Another related article was also published on July 5, 1975 Lancet

Medicine is complex                                                                                                                          Like Oppenheimer told his students at U.C. Berkeley, “I can make it clearer, but I cannot make it simpler.”  I am hoping you would paraphrase Enrico Fermi that before you read this article, you’re confused, and after reading this article, you’re still confused, but at a higher level.