The Genetic Basis of Cancer

the basis ofbasis of Cancer is inherently a genetic disease. In this infographic, we will explore the genetic basis of cancer, understanding how mutations in different types of genes can lead to cancer development, how these cancers can be sporadic or hereditary and how this can guide diagnosis and treatment. Mutations can drive cancer developmentcancer development Estimates suggest that between 1–10 mutations Unlike other diseases on average are required (like cystic fibrosis, for to cause cancer, but this example) no single gene can differ between cancer causes cancer. They types. Research suggests contribute towards rather around 4 driver mutations for than cause cancer. liver cancer or about 10 for colorectal cancer. healthy cellshealthy cells malignant cellsmalignant cells 1st mutation 2nd mutation 3rd mutation Nth mutation These changes can happen at random, caused by mistakes in the machinery that replicates our DNA as our cells divide. They can also be caused by factors in our environment or lifestyle. Human papilloma virus (HPV) and cervical cancer Ultraviolet (UV) Tobacco smoking radiation and and lung cancer skin cancer Three main types of genes in cancerof cancer 11 22 33 Tobacco smoking and lung cancer Human papilloma virus (HPV) and cervical cancer Protro-oncogene Overactive/constitutively active oncogene Inactivated tumor suppressor gene Tumor suppressor gene non-small cell lung cancers (30%) pancreatic ductal adenocarcinomas (up to 95%) colorectal cancers (40%) Ultraviolet (UV) radiation and skin cancer Three key types of genes are involved in cancer development – oncogenes, tumor suppressor genes 1 11 22 33 Tobacco smoking and lung cancer Human papilloma virus (HPV) and cervical cancer Protro-oncogene Overactive/constitutively active oncogene Inactivated tumor suppressor gene Tumor suppressor gene non-small cell lung cancers (30%) pancreatic ductal adenocarcinomas (up to 95%) colorectal cancers (40%) Ultraviolet (UV) radiation and skin cancer Three key types of genes are involved in cancer development – oncogenes, tumor suppressor genes and stability/repair genes. Oncogenes are mutated genes that become over-activated or continuously activated. Prior to mutation, they are called proto-oncogenes, and function as part of normal cellular processes such as growth and division – but the mutated oncogene can lead to uncontrolled proliferation and cancer development. Protro-oncogene Overactive/constitutively active oncogene KRAS is one of the most frequently mutated oncogenes – it is commonly found in: non-small cell lung colorectal cancers (40%) pancreatic ductal cancers (30%) adenocarcinomas (up to 95%) 2 Tumor suppressor genes protect against cancer development, and mutations that impair their function/activity can lead to cancer. Tumor suppressor Inactivated tumor gene suppressor gene p53 the “guardian of the genome”, induces programmed cell death – apoptosis – in damaged cells, to prevent them from becoming cancerous. Around one in two cancers have loss-of-function mutations in p53. 3 Stability/repair genes work differently. Repair genes protect the genome against genetic alterations, and stability genes help to control larger portions of DNA – such as ensuring that chromosomes are tightly regulated during cell division Together, stability and repair genes minimize genetic alterations. Therefore, when they are inactivated, alterations accumulate faster. A delicate balance Cells must maintain a delicate balance, and alterations to proto-oncogenes and tumor suppressor genes can result in uncontrolled cell growth. Proto-oncogene Overactive normal cell cancer cell oncogene Tumor suppressor gene Inactivated tumor suppressor gene cancer cell cancer cell SporadicSporadic vs hereditary cancershereditary cancers Mutations in germline cells can be passed down to offspring, and are copied into every cell in the body, predisposing them to cancer – these are “hereditary” cancers. For example: Though cancer itself mutations in tumor cannot be passed down suppressor genes BRCA1 and BRCA2 are the from parents to children, most common causes of hereditary breast up to 10% of cancers may cancer. Mutations can render BRCA1/2 unable be caused by inherited to restrain uncontrolled cell growth, leading to genetic changes. This gives cancer development. Women who carry mutant cancer development a BRCA1/2 have a significantly higher risk of breast head start, but additional and ovarian cancer, known as hereditary breast mutations are required to and ovarian cancer syndrome (HBOC), and can turn a cell cancerous. develop cancer at a much younger age. Women’s breast cancer risk (by age 70–80)(80) 55-72% Mutated BRCA1 45-69% Mutated BRCA2 12% Normal BRCA1/2 Mutations in the somatic cells are not passed down but can lead to tumor formation – these are “sporadic” cancers. The mutation is acquired, not inherited, and is only found in the tumor cells. Sporadic cancerSporadic cancer inherited cancerinherited cancer Cancer diagnosis No cancer diagnosis Guiding diagnosis and treatmentand treatment As our knowledge of the genetic basis has grown, so has our ability to treat cancer. Genetic testing has paved the way for precision medicine approaches using next-generation sequencing (NGS) technologies such as whole-genome or whole-exome sequencing. For example: the BRAF V600E mutation is found in almost half of all melanomas. Normal BRAF signaling controls cell growth and proliferation, but the V600E mutation increases its activity and drives cancer development. The mutated BRAF protein can be targeted using a drug called vemurafenib, which inhibits BRAF and its oncogenic signaling. ras-gtpras-gtp braf v600ebraf v600e mek erk Cell proliferation/cancer development Vemurafenib Overall, advances in our knowledge of the genetic basis of cancer can help to guide earlier diagnosis and improve treatments to benefit patients.