How do genes correlate with cancer?

How do genes correlate with cancer?

Cancer is the second leading cause of death in the United States.

It is well established that many major types of cancer (e.g., breast, colon, prostate, ovarian) cluster strongly in families.

Clustering is caused by both inherited genes and shared environmental factors.

Numerous cancer-causing genes are being isolated but environmental and lifestyle factors play an important role in causing cancer.

For example, tobacco use is estimated to account for one-third of all cancer cases in the United States, making it the most important known cause of cancer.

Recently developed techniques, including large-scale DNA sequencing, have identified hundreds of genes that are mutated in various cancers. Some of these genes contribute directly to a growth advantage in tumors and are considered primary causes of cancer.

150 such driver genes have been described.

A much larger number of genes undergo somatic mutations during tumorigenesis, but these genes do not directly confer a growth advantage to cells; these are termed passenger genes.

The gene responsible for retinoblastoma, which normally acts as a �brake� on cell division, is an example of a well-known driver gene.

The APC gene is another example.

Many types of cancer, such as retinoblastoma or familial adenomatous polyposis, are relatively rare but study of the causative genes has provided many important insights into the nature of carcinogenesis in general. This can lead to more effective treatment and prevention of all cancers.

Environmental factors cause cancer by creating somatic mutations in specific cell types. Thus, cancer can be caused both by inherited genetic variants and by non-inherited somatic mutations acquired during an individual�s lifetime.

Different types of cancers caused by inherited genetic variants and non-inherited somatic mutations are presented.

Breast Cancer

It is the most common cancer among women, with 82% of breast cancers diagnosed among women aged 50 years and older and has surpassed lung cancer.

13% of women (1 in 8) will be diagnosed with invasive breast cancer in their lifetime.

It aggregates strongly in families; example, 
if a woman has one affected first-degree relative, her risk of developing breast cancer doubles and it increases further if the age of onset in the affected relative is early and if the cancer is bilateral (tumors in both breasts).

An autosomal dominant form of breast cancer accounts for approximately 5% to 10% of breast cancer cases in the United States. Genes responsible for this form of breast cancer are identified on chromosomes 17 (
BRCA1
) and 13 (
BRCA2
) and can be tested for inherited cancer-causing mutations.

Women who inherit a mutation in 
BRCA1 or BRCA2
 experience a 50% to 80% lifetime risk of developing breast cancer.

In a seminal paper of more than 8,000 unselected cases of breast or ovarian cancer, the average cumulative risk of developing breast cancer with a 
BRCA1
 mutation was 65%.

BRCA1
 mutations also increase the risk of ovarian cancer among women (39%), and they confer a modestly increased risk of prostate and colon cancers.

BRCA2
 mutations also confer an increased risk of ovarian cancer (11%).

5% to 8% of males who inherit a 
BRCA2
 mutation will develop breast cancer, representing a 100-fold increase over the risk in the general male population.

Evaluation of the 
BRCA1
 and 
BRCA2
 gene products, which are involved in deoxyribonucleic acid (DNA) repair, is yielding valuable evidence on the etiology of breast cancer in general.

BRCA1
 and 
BRCA2
 mutations are the most known causes of inherited breast cancer but this disease also can be caused by inherited mutations in several other genes.

For example, 
ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11,
 and 
TP53
.

Germline mutations in a tumor-suppressor gene called PTEN are responsible for Cowden diseases.

It is characterized by multiple benign tumors and an increased susceptibility to breast cancer.

Despite the significance of these genes, it should be emphasized that more than 90% of breast cancer cases are not inherited as mendelian diseases.

Colorectal Cancer

It is second only to lung cancer in the number of cancer deaths occurring annually in the United States, with 148,000 new cases and 53,000 deaths annually.

1 in 21 Americans will develop colorectal cancer.

Like breast cancer, it clusters in families (in fact, familial clustering of this form of cancer was reported in the medical literature as early as 1881).

The risk of colorectal cancer in people with one affected first-degree relative is two to three times higher than that in the general population.

This familial aggregation is caused in part by subsets of colorectal cancer cases that are inherited as single-gene traits.

For example, 
familial adenomatous polyposis
 occurs in approximately 1 in 8000 Whites.

The gene responsible for this disorder, 
APC
, encodes a tumor suppressor.

Somatic mutations of 
APC
 are found in at least 85% of all colon tumors.

Inherited 
APC
 mutations cause rare familial adenomatous polyposis, but somatic mutations are involved in majority of all common colorectal cancers.

Among hereditary forms of colorectal cancer, the most frequent is hereditary nonpolyposis colorectal cancer.

It accounts for 3% to 4% of colorectal cancer cases and is caused by mutations in any of six genes.

Research shows that all these genes are involved in the vital process of DNA repair.

When this function is compromised, cancer-causing mutations can persist in cells, leading eventually to growth of a tumor.

Other colorectal cancer cases are likely to be caused by a complex interaction of multiple genes.

Environmental factors, such as a high-fat, low-fiber diet, are thought to increase the risk of colorectal cancer.

Prostate Cancer

It is the second most diagnosed cancer in men (after skin cancer), with 165,000 new cases annually in the United States and a lifetime risk of 11%.

It is second only to lung cancer as a cause of cancer death in men, causing more than 30,000 deaths each year.

Having an affected first-degree relative increases the risk of developing prostate cancer by a factor of 2 to 3, and the heritability of prostate cancer is estimated to be approximately 40%.

The relatively late age of onset of most prostate cancer cases (median age 72 years) makes genetic analysis especially difficult.

Loss of heterozygosity has been observed in several genomic regions in prostate tumor cells, possibly indicating the presence of genetic alterations in these regions.

Genome-wide association studies have identified several dozen polymorphisms associated with prostate cancer risk.

Several of these are in chromosome 8q24, which contains polymorphisms associated with several other cancers as well (colon, pancreas, and esophagus).

Although the 8q24 region contains no protein-coding genes, it contains enhancer elements that affect expression of the MYC oncogene, located approximately 250 kilobytes (kb) from 8q24.