CANCER AND CANCER PREDISPOSITION
Cancer is a type of disease caused by a group of cells that develop, spread and escape cell death due to genetic disorders occurring at any stage of normal cell development. It is a multifactorial disease that may be induced by combination of lifestyle, environmental exposures, and genetic background. People with cancer are mainly developing the disease due to environmental factors such as chemical exposures, sunlight etc, or habits such as smoking, diet etc. Based on the literature, it is stated that only 5-10% of the cancers are hereditary cancers while the remaining are non-hereditary, also known as sporadic cancers. cancers are a variety of malignancies that may affect different systems, organs, and tissues. These malignancies occur based on the age, sex, genetic background, environmental factors, and habits.
Based on where the development of the malignancy starts, cancers may be classified. For example, malignancies occurring in the milk duct cells or lobules cause breast cancer (mostly in females). Moreover, lung cancer is another example of adult cancers which is mostly associated with smoking. Another example of adult cancers is colorectal cancer which is caused by the abnormal cell proliferation in the lining of the colon or rectum, also called as polyps. As it was stated before, many adult cancers are sporadic. Also, in hereditary cancers, age onset of the malignancies is lower than the sporadic cancers due to the positive genetic background that allow cells to evade cell death.
Childhood cancers are seen as more rare than adult cancers due to cellular differences, immune system, less exposure to carcinogenic chemicals, and early detection & intervention. As children and adolescents have less mutation load compared to adults, furthermore, the immune system of the children and adolescents works more efficiently than the adult immune systems to detect and eradicate the cancerous cells. Moreover, children and adolescents are usually exposed to carcinogens less than adults which causes less incidence of cancer in children and adolescents. Lastly, childhood cancers are usually more aggressive than the adult cancers which allow physicians to diagnose and treat the disease earlier. When it comes to the genetic background of childhood cancers, it is stated that 10-15% of the childhood cancers are hereditary, whereas 5-10% in adults.
In 1971, a physician called Dr. Alfred G. Knudson published an article based on his studies on retinoblastoma. This study suggests “two-hit theory”: as the “first hit”, the patient inherits one allele from one parent, thus, increasing the risk of cancer development in hereditary cancer cases. However, the other or “healthy” allele of the gene mutates and leads to “second hit”. The study clarifies why cancer in hereditary/sporadic cases differ in terms of onset and prevalence. Cancer typically strikes earlier in life and may run in families more frequently in hereditary cases, when one mutation is already present from birth. In sporadic examples, which might take longer and be less frequent, both hits must happen separately in a cell within a person's lifespan. Knudson's two-hit theory has been crucial to cancer research and genetic counseling since it reveals the fundamentals of how genetic alterations contribute to the development of cancer.
After the advancements in the molecular genetics and sequencing technologies, we identified more genes that are responsible for familial malignancies, and they are named as predisposition genes. Cancer predisposition may arise from the certain types of variants in different cancer predisposition genes. For example, as a well-known cancer predisposition genes BRCA1 and BRCA2, their deleterious variants are known to cause Hereditary Breast and Ovarian Cancer Syndrome (HBOC). People with HBOC have greater risk of developing breast and ovarian cancers compared to people without HBOC. Furthermore, MLH1, MSH2, MSH6 and PMS2 genes are responsible for DNA mismatch repair, and deleterious variants are associated with the Lynch Syndrome and colorectal malignancies. Another example is the TP53 gene which is associated with the Li-Fraumeni syndrome. All of the indicated syndromes are associated with the cancer predisposition which are only a few examples of cancer predisposition syndromes. Based on the advancements in the sequencing technologies, it is for sure that there are other genes and cancer predisposition syndromes to be identified in the future.
References:
Chial, H. (2008). Tumor suppressor (TS) genes and the two-hit hypothesis. Nature Education, 1(1), 177.
Wang, Q. (2016). Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes. Acta Pharmacologica Sinica, 37(2), 143-149.
Park, S., Supek, F., & Lehner, B. (2018). Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nature communications, 9(1), 2601.
