CHAPTER 1 OBJECTIVE: to have a well-rounded understanding the biology of cancer, what causes cancer and how it is categorized. You will gain an understanding of:

• Causes
• Categories
• Genetics

OUR GOAL: is to have a general understanding of cancer as a disease

This information is an excerpt from the Module 1 PDF, a 180 page document with the latest cancer research and references listed.

VIEW THE FULL MODULE 1 PDF HERE

MODULE 1, CHAPTER 1 EXCERPT

Cancer is a major public health challenge. In 2020, an estimated 19.3 million people around the world were diagnosed with cancer, and almost 10 million died from the disease. By 2040, those figures will nearly double, with the greatest increase in low and middle-income countries, where more than two thirds of the world's cancers will occur. Cancer is the cause of about 30% of all premature deaths from noncommunicable diseases among adults aged 30-69. One third to one half of cancer cases could be prevented by reducing exposure to known risk factors.

The most frequently diagnosed cancer is breast cancer (11.7% of all cases), followed by lung (11.4%) and colorectal cancers (10%). Lung cancer is the leading cause of death from cancer (24% of all deaths), followed by colorectal (9.4%) and liver cancers (8.3%). The most common cancer types vary among countries, with certain cancers, such as cervical cancer and Kaposi sarcoma, much more common in countries at the lower end of the human development index (HDI) than in high-HDI countries. Globally, the cancer burden will increase by at least 60% over the next two decades, straining health systems and communities. Cancer occurs in more than 400,000 children every year worldwide, and the rate is expected to increase.

For both sexes combined, roughly one‐half of the cases and over one‐half of the cancer deaths in the world occurred in Asia in the year 2020, in part because close to 60% of the global population resides there. Europe accounts for 22.8% of the total cancer cases and 19.6% of the cancer deaths, although it represents only 9% of the global population, followed by North Americas 13.3% of incidence and Latin America and the Caribbean's 7.2% of mortality worldwide. In contrast to other regions, the shares of cancer deaths in Asia (58.3%) and Africa (7.1%) are higher than the shares of incidence (49.3% and 5.7%, respectively) because of the different distribution of cancer types and higher case fatality rates in these regions. By 2040, the global burden is expected to grow to 28.4 million new cancer cases and 16.3 million cancer deaths simply due to the growth and aging of the population.

WHAT IS CANCER?

The term "cancer" refers to a group of diseases in which abnormal (malignant) cells divide and form additional abnormal cells without any order or control. There are more than 100 types of cancer. Types of cancer are usually named for the organs or tissues where the cancers form. For example, breast cancer starts in cells of the breast, and prostate cancer starts in cells of the prostate. Cancers also may be described by the type of cell that formed them, such as an epithelial cell or a squamous cell. Cancer can start almost anywhere in the human body, which is made up of trillions of cells. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer this balance is disrupted.

Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive. One important difference is that cancer cells are less specialized than normal cells. Normal healthy cells mature into specific cell types with distinct functions, cancer cells do not. Cancer cells continue to divide without stopping. Cancer cells also can ignore signals that would normally tell cells to stop dividing (programmed cell death, or apoptosis), which the body uses to get rid of unneeded cells.

Angiogenesis, the growth of new capillary blood vessels in the body, is a natural process used by the body for healing and reproduction. The body controls angiogenesis by producing a precise balance of growth and inhibitory factors in healthy tissues. Abnormal blood vessel growth, either excessive or insufficient, is now recognized as an underlying factor in many conditions, including cancer, skin diseases, age-related macular degeneration, diabetic ulcers, cardiovascular disease, stroke, and many others. Cancerous tumors release angiogenic growth factor proteins that stimulate blood vessels to grow into the tumor, providing it with oxygen and nutrients. Cancer cells may be able to influence the normal cells, molecules, and blood vessels that surround and feed a tumor. They can induce nearby normal cells to form blood vessels that will supply the tumor(s) with oxygen and nutrients, that are required for growth.

Cancer cells are also often able to circumvent the immune system by "hiding" from the immune system. Tumors can also use the immune system to stay alive and grow by keeping the immune system from killing cancer cells.

Angiogenesis inhibitors, also called anti-angiogenics, are drugs that block angiogenesis. Blocking nutrients and oxygen from a tumor "starves" it. These drugs are an important part of treatment for some types of cancer.

EXAMPLES OF ANGIOGENESIS INHIBITORS ARE: 

•        Inlyta® (Axitinib) - treatment option for kidney cancer

•        Avastin® (Bevacizumab)- treatment option for colorectal, kidney, and lung cancers

•        Cometriq® (Cabozantinib) - treatment option for medullary thyroid cancer and kidney cancer

•        Everolimus® (Afinitor, Zortress) - treatment option for kidney cancer, advanced breast cancer, pancreatic neuroendocrine tumors (PNETs), and subependymal giant cell astrocytoma, which is a rare type of noncancerous brain tumor

•        Revlimid® (Lenalidomide) - treatment option for multiple myeloma, tumors involving cells that normally produce antibodies, and mantle cell lymphoma, which is a type of non-Hodgkin lymphoma

•        Lenvima® (Lenvatinib) - treatment option for endometrial carcinoma, hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer

•        Votrient® (Pazopanib) - treatment option for kidney cancer and advanced soft tissue sarcoma

•       Cyramza® (Ramucirumab) - treatment option for advanced stomach cancer; gastroesophageal junction adenocarcinoma, a cancer located where the stomach joins the esophagus; colorectal cancers; and non-small cell lung cancers

•       Stivarga® (Regorafenib) - treatment option for colorectal cancer and gastrointestinal stromal tumors (GIST)

•       Nexavar® (Sorafenib) - treatment option for kidney, liver, and thyroid cancers

•       Sutent® (Sunitinib Malate) - treatment option for kidney cancer, PNETs, and GIST

•       Thalomid®/Synovir® (Thalidomide) - treatment option for multiple myeloma. Women who are pregnant should not take this drug because it is prove to harm fetuses.

•       Caprelsa® (Vandetanib ) - treatment option for medullary thyroid cancer

•       Zaltrap®(Ziv-aflibercept ) - treatment option for colorectal cancer

Because many of the body's normal functions depend on angiogenesis, angiogenesis inhibitors can cause a wide range of side effects including:

•        High blood pressure

•        Biochemical hypothyroidism

•        Hand-foot syndrome - this causes tender, thickened areas on the palms and soles. Sometimes, it causes blisters.

•        Diarrhea

•        Fatigue

•        Low blood counts

Problems with wound healing or cuts reopening

Although common, these side effects do not happen with every drug or every person, and medicines are available to help manage these side effects. Rare side effects are:

•        Serious bleeding

•        Clots in the arteries with resultant heart attack or stroke

•        Heart failure

•        Blood clots

Holes in the intestines (bowel perforations)

DEVIATION FROM NORMAL CELL GROWTH

Cancer tissue has a distinctive appearance when viewed under a microscope. Pathologists will look for a large number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of normal tissue organization, and a poorly defined tumor boundary.

Sometimes pathologists will detect a condition known as "hyperplasia." This refers to tissue growth based on an excessive rate of cell division, leading to a larger than usual number of cells. Everything else in the cells' structure seems to remain normal and potentially reversible. Hyperplasia can be a normal tissue response to an irritating stimulus; for example, a callus that forms on your hand when you begin playing tennis on a regular basis.

Another non-cancerous condition is called "dysplasia." This, too, is an abnormal type of cell proliferation characterized by loss of normal tissue arrangement and cell structure.

Often these cells will revert to normal behavior but occasionally they become malignant over time.

These areas are usually closely monitored by a professional in case they need treatment. The most severe cases of dysplasia are sometimes referred to as "carcinoma in situ." This term refers to an uncontrolled growth of cells that remains in its original location. It does, however, have the potential to develop into an invasive malignancy and, is therefore, usually removed surgically when possible. Lastly, there is invasive cancer. Unlike carcinoma in situ, this cancer has spread beyond its original location and has begun to infiltrate into other, previously healthy, tissue. These tumors tend to grow more quickly, spread to other organs more frequently, and be less responsive to therapy. These cancers are surgically removed when possible and often accompanied by radiation and/or chemotherapy to kill any cancerous cells that have spread outside of the tumor.

Cancers are divided into several categories with carcinomas making up 80-90% of all cancers.

1.    Carcinomas - cancers that arise in the epithelium, the membranous tissue that forms the inner lining and outer covering of organs, glands, and vessels, as well as the surface layer of the skin. Carcinomas include lung, breast, cervical, prostate, and colon cancer. Carcinomas that begin in different epithelial cell types have specific names:

-       Adenocarcinoma - is a cancer that forms in epithelial cells that produce fluids or mucus. Tissues with this type of epithelial cell are sometimes called glandular tissues. Most cancers of the breast, colon, and prostate are adenocarcinomas.

-       Basal cell carcinoma - is a cancer that begins in the lower or basal (base) layer of the epidermis, which is a person's outer layer of skin.

-       Squamous cell carcinoma - is a cancer that forms in squamous cells, which are epithelial cells that lie just beneath the outer surface of the skin. Squamous cells also line many other organs, including the stomach, intestines, lungs, bladder, and kidneys. Squamous cells look flat, like fish scales, when viewed under a microscope. Squamous cell carcinomas are sometimes called epidermoid carcinomas.

-       Transitional cell carcinoma - is a cancer that forms in a type of epithelial tissue called transitional epithelium, or urothelium. This tissue, which is made up of many layers of epithelial cells that can get bigger and smaller, is found in the linings of the bladder, ureters, and part of the kidneys (renal pelvis), and a few other organs. Some cancers of the bladder, ureters, and kidneys are transitional cell carcinomas.

The following five categories make up the remaining 10%:

•        Sarcomas - cancers in the bone, cartilage, tendons, ligaments, fat, muscle, and blood & lymph vessels. Osteosarcoma is the most common cancer of bone.

•        Leukemias - cancers that begin in the blood-forming tissue of the bone. These cancers do not form solid tumors. Large numbers of abnormal white blood cells (leukemia cells and leukemic blast cells) build up in the blood and bone marrow and "crowd-out" normal blood cells. Due to the low level of normal blood cells, it can make it harder for the body to get oxygen to its tissues, control bleeding, or fight infections. Examples include:

-    Myelogenous or granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series)

-    Lymphatic, lymphocytic, or lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series)

-    Polycythemia vera or erythremia (malignancy of various blood cell products, but with red cells predominating)

•        Lymphomas (including multiple myeloma) - cancers that begin in lymphocytes (T cells or B cells). These are disease-fighting white blood cells that are part of the immune system. In lymphoma, abnormal lymphocytes build up in lymph nodes and lymph vessels, as well as in other organs of the body. There are two main types of lymphomas.

-    Hodgkin lymphoma - people with this disease have abnormal lymphocytes that are called Reed-Sternberg cells. These cells usually form from B cells.

-    Non-Hodgkin lymphoma - this is a large group of cancers that start in lymphocytes. The cancers can grow quickly or slowly and can form from B cells or T cells.

•        Melanomas - cancer that forms in the skin cells that produce pigment responsible for skin color

•        Gliomas - these cancers form in the brain and spinal cord. They are named based on the type of cell in which they formed and where the tumor first formed in the central nervous system. For example, an astrocytic tumor begins in star-shaped brain cells called astrocytes, which help keep nerve cells healthy.

WHAT CAUSES CANCER? 

Cancer is a genetic disease caused by changes to genes that control the way our cells function; particularly how they grow and divide. Genetic changes may be inherited from our parents (only 5-10% of all cases). They can also arise during a person's lifetime as a result of errors that occur as cells divide or because of damage to DNA caused by certain environmental exposures (acquired changes).

Cancer-causing environmental exposure that leads to oxidative stress includes chemicals in tobacco smoke, radiation, pesticides, viruses, food additives and coloring, and more.

Chemicals and radiation that can cause cancer are known as "carcinogens." Carcinogens initiate a series of genetic alterations or mutations and encourage cell proliferation. This usually doesn't happen overnight. Sometimes several decades can pass between exposure to a carcinogen and the onset of cancer. Since exposure to carcinogens is responsible for triggering most cancers, we can reduce our risk by taking steps to avoid such agents whenever possible. The use of tobacco products has been implicated in one out of every three cancer deaths. Despite the Surgeon Generals' repeated warnings, as well as the fact that smoking is the largest single cause of death from cancer, the tobacco industry continues to thrive. Avoiding tobacco products, cigarettes, cigars, and chewing tobacco is the single most effective lifestyle decision you can make to prevent cancer.

Although it is usually not life-threatening, skin cancer caused by exposure to sunlight is the most frequently observed type of cancer. Most of us do not take skin cancer very seriously because it is often easy to cure. Melanoma, a more serious form of skin cancer, also associated with sun exposure, is potentially lethal. Once again, we choose to ignore the repeated and ever-present warnings to stay out of the sun and continue to bask in the sun's glory for hours on end. Risk of skin cancer can be greatly reduced by wearing clothing to shield the skin from ultraviolet radiation, wearing protective sunscreen or by avoiding direct sun exposure altogether.

Actions can also be taken to avoid exposure to some of the viruses that are associated with cancers. The most common of which is the human papillomavirus (HPV) which is involved in the transmission of cervical cancer. "Safe sex," including limiting exposure to multiple sex partners, is the best way to prevent this virus which is sexually transmitted. Many carcinogens have become "occupational" hazards to those who encounter them on a regular basis. These include arsenic, asbestos, benzene, chromium, leather dust, naphthylamine, radon, soots, tars, oils, vinyl chloride, and wood dust. Workers who are exposed to these chemicals have a higher incidence of cancer.

The increase in identifiable cancer cases is due largely in part to increased life span because cancer is more prevalent among older people. Obesity (being extremely overweight) raises the risk of type II diabetes, high blood pressure, heart disease, and cancer. The connection between type 2 diabetes and cancer is complex, involving both genetic and lifestyle factors. The two diseases - diabetes and cancer - share several key risk factors, including obesity and lack of physical activity. Excess body fat can lead to insulin resistance, a risk factor for type 2 diabetes. It also can trigger chronic inflammation, and increased estrogen production which, along with insulin resistance, are key contributing factors in the development of tumorous cells.

These connections are the focus of a study published in The Lancet Diabetes and Endocrinology. The researchers looked at data on 12 types of cancer from 175 countries and found approximately six percent of new cancer cases worldwide (nearly 800,000) in 2012 were caused by the combined effects of diabetes and overweight or obesity. Among individual risk factors, being overweight was responsible for twice as many cancers (3.9 percent) as diabetes (2%). AICR research shows that adults with diabetes have about twice the risk of developing cancers of the liver, pancreas, and endometrium. There's a clear but smaller increase in risk for colon and breast cancers. Excess body weight was responsible for 3.9% of cancer globally (544,300 cases in 2012) according to a new report.

In men, liver cancer was the most common cancer caused by diabetes and high BMI, accounting for 126,700 cases, and colorectal cancer was second, accounting for 63,200 of cancer cases In women, 147,400 breast cancer cases constituted 29.7% of all cancers attributable to diabetes and high BMI.149 Endometrial cancer was second, accounting for 121,700 new cancer cases or 24.5 per cent or all diabetes and high BMI related cancers.149

In addition, being overweight and obesity cause 15% to 20% of all cancer-related deaths each year.150 Several studies have explored how being overweight or obese may increase cancer risk and growth.150 People who are obese have more fat tissue, which can produce hormones, such as insulin or estrogen, and may cause cancer cells to grow. How much a person weighs throughout various points in his or her life may also affect the risk for cancer. Research has shown that the following are modestly associated with an increased risk:

• HIgh birth weight
• Weight gain during adulthood
• Gaining and losing weight repeatedly

Cancer cells come in all different shapes and sizes and are classified by their aggressiveness and from the tissue where they originate. Cancer cells that essentially resemble their non-cancerous counterparts and can still perform some of their normal functions are described as well differentiated. On the flip side, the cells that are identified by their disorganized structure and their ability to divide rapidly and chaotically are known as poorly differentiated cells. A tumor that remains confined to its original, or primary location, is referred to as localized. There are two ways that a cancer can spread; it can grow straight through the primary organ and directly into adjacent tissue (referred to as a local extension or regional disease), or in metastatic cancer, a colony of malignant cells can break away and ride the circulatory system to nearby lymph nodes or a distant organ where it forms a secondary cancer. Sometimes, despite batteries of tests, a metastatic tumor is diagnosed, but no primary tumor is found. When this happens, the cancer is declared a cancer of unknown primary origin.

GENETICS

There are at least 50 hereditary cancer susceptibility syndromes that have been identified; although heredity only accounts for about 5-10% of all cancers. In these cases, the cancer is caused by an abnormal gene that is being passed along from generation to generation. This takes place when an abnormal gene that can lead to cancer is inherited.

Genes are pieces of DNA. They contain the instructions on how to make the proteins the body needs to function, when to destroy damaged cells, and how to keep your body's cellular composition in balance. They control everything that makes you YOU and they can also affect your risk of getting cancer. When there is an abnormal change in a gene it's called gene mutation.

The 2 types of mutations are inherited and acquired (somatic):

• An inherited gene mutation is one that is transmitted through genes that have been passed from parents to their offspring

• Acquired (somatic) mutations are changes in DNA that develop throughout a person's lifetime

We are born with two copies of most genes - one from our mother and one from our father. When we inherit an abnormal copy of a gene, our cells already start out with one mutation. If the other copy of the gene stops working (because of an acquired mutation, for example), the gene can stop functioning altogether. When the gene that stops working is a cancer susceptibility gene, cancer may develop. Some cancer susceptibility genes function as tumor suppressor genes (normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die - a process known as apoptosis or programmed cell death).

When tumor suppressor genes do not work properly, cells can grow out of control, which can lead to cancer. Many family cancer syndromes are caused by inherited defects of tumor suppressor genes. Cancers that are caused by inherited genes tend to occur earlier in life than those that are acquired.

When many people in one family have cancer, the assumption is that it is inherited however, it is more likely that it is due to chance or exposure to a common toxin. Less often, these cancers may be caused by an inherited gene mutation causing a family cancer syndrome. The following list (provided by the American Cancer Society) are cancers that are more likely to occur from an inherited gene:

• Many cases of an uncommon or rare type of cancer
• Cancers occurring at younger ages than usual
• More than one type of cancer in a single person (like a woman with both breast and ovarian cancer)
• Cancers occurring in both of a pair of organs (both eyes, both kidneys, both breasts)
• More than one childhood cancer in a set of siblings (like sarcoma in both a brother and a sister)
• Cancer occurring in the sex not usually affected (like breast cancer in a man)

Cancer in a parent, brother or sister is more cause for concern than cancer in a more distant relative. Even if a gene mutation is present, the chance of you becoming diagnosed is reduced with more distant relatives. Having two relatives with cancer is more concerning if the people are related to each other. For example, if both relatives are your father's sisters it carries more weight than if one was your father's sister and the other was your mother's sister.

Having several different kinds of cancer among family members is not as concerning as many family members having the same type of cancer. There are, however, some family cancer syndromes, in which a few types of cancer seem to go hand-in-hand (breast cancer and ovarian cancer run together in families with hereditary breast and ovarian cancer syndrome, colon and endometrial cancers tend to go together in a syndrome called hereditary non-polyposis colorectal cancer - Lynch syndrome).

The age at which someone is diagnosed is also important. For example, colon cancer is rare in people under thirty. Having two or more cases in close relatives under thirty years of age could be a sign of an inherited cancer syndrome. On the other hand, breast cancer is very common in menopausal women. If both your mother and her sister were found to have breast cancer when they were in their 50s, it is less likely to be due to an inherited gene change.

FAMILY CANCER SYNDROMES 

1. Ataxia-Telangiectasia - affects the nervous system, immune system and other body systems. It can cause a loss of balance, poor coordination (ataxia), frequent infections, red eyes (due to widening of blood vessels) and abnormal eye movements. Ataxia-telangiectasia increases the risk of leukemia, lymphoma and breast cancer. It is caused by a mutation of the ATM gene, which normally repairs damage to DNA.

2. Basal Cell Nevus Syndrome - is also called Gorlin syndrome or nevoid basal cell carcinoma syndrome. It is usually caused by a mutation in PTCH1, a tumor suppressor gene. This syndrome causes different problems with the skin, eyes, nervous system, endocrine glands and jawbone. People may also have a larger head size than average (called macrocephaly).

Basal cell nevus syndrome increases the risk of non-melanoma skin cancer, brain and spinal cord cancer and soft tissue sarcoma.

3. Beckwith-Wiedemann Syndrome - causes the body to grow more than it should or asymmetrically during development and into childhood. Newborns may have hypoglycemia. Children with Beckwith-Wiedemann syndrome have an increased risk of developing Wilms tumor (a type of kidney cancer that affects children), hepatoblastoma (a rare type of liver cancer that affects children), neuroblastoma, rhabdomyosarcoma, and adrenal gland cancer.

Another option for people with colorectal or endometrial cancer is to have the tissue biopsied to look for changes that may be caused if one of these genes is faulty. These changes are known as microsatellite instability (or MSI). If no MSI is found, it implies that HNPCC is not present and that the genes that would be likely to cause it are normal.

If MSI is present, they may have HNPCC, and so are referred for genetic counseling and possible testing. Someone who is known to carry an HNPCC gene mutation may start screening for colorectal in their early 20s.44 Women with HNPCC may start screening for endometrial cancer or undergo a hysterectomy. If someone in a family is found to have HNPCC, it means that their close relatives (parents, siblings, and children) have a 50% chance of having a mutation, too.44, 45, 47

Hereditary Retinoblastoma - is caused by an inherited RB1 gene mutation or an RB1 gene mutation that happens in the egg or sperm before conception and is passed on to the child. Children with hereditary retinoblastoma will usually develop retinoblastoma in both eyes, and have an increased risk of developing bone cancer, soft tissue sarcoma and melanoma later in life.

Juvenile Polyposis Coli - is a rare, childhood-onset disease and an autosomal dominant disorder that results from mutations in various cancer susceptibility genes, including the SMAD4/DPC4 and BMPR1A genes. The condition is associated with the development of hamartomatous polyps that can be present throughout the gastrointestinal tract. Juvenile polyposis is associated with an increased chance for gastrointestinal and pancreatic cancers. Most patients appear to be sporadic cases (happening for the first time in a family).

Li-Fraumeni Syndrome - is a rare syndrome that can lead to the development of a number of: osteosarcoma, soft-tissue sarcomas, leukemia, brain & central nervous system cancers, cancer of the adrenal cortex, and breast cancer. The cancers most often occur in childhood,

although breast cancer occurs in young adults. People with Li-Fraumeni can also be affected by more than one cancer in their lifetime. They also seem to be at higher risk of cancer from radiation therapy, and so doctors treating these patients may try to avoid giving them radiation when possible.

This syndrome is most often caused by inherited mutations in the gene for p53 (TP53, a tumor suppressor gene).41, 45, 47 A normal gene for p53 stops the growth of abnormal cells. It can also be caused by mutations in a gene called CHEK2.

22. Lynch Syndrome - about 2% to 3% of colorectal cancers are caused by Lynch syndrome. People with Lynch syndrome (also called hereditary non-polyposis colorectal cancer, or HNPCC) have a mutation in 1 out of 4 genes that normally correct mistakes when DNA is copied during cell division. These genes are called DNA mismatch repair (MMR) genes. People with Lynch syndrome have a high risk of colorectal cancer. When colorectal cancer develops in people with Lynch syndrome, it usually happens before age 50. Lynch syndrome also increases the risk of endometrial cancer, pancreatic, ovarian, stomach, and small intestine cancers.

23. Multiple Endocrine Neoplasia (MEN) Syndromes - received their name because they predispose people to develop tumors of the endocrine glands. The endocrine system is comprised of glands that secrete hormones into the bloodstream that control numerous processes within the body. The endocrine system is instrumental in regulating mood, growth and development and metabolism, as well as sexual function and reproductive processes. The major glands of the endocrine system affected by the MEN syndromes are the pituitary, thyroid, parathyroid, adrenals and pancreas. Currently, there are two distinct MEN syndromes: MEN1 and MEN2.In some ways, the two syndromes are similar, but there are important differences.

24. MUTYH-Associated Polyposis (MAP) - is a rare, hereditary condition in which a person has numerous adenomatous polyps (abnormal tissue growths) in their colon and rectum. People with harmful mutations in the MUTYH (formerly called MYH) gene can develop several different types of polyps in their large intestine, including adenomas, sessile serrated polyps, and hyperplasic polyps. Most people who have MAP usually develop between 10 and 100 polyps. In rare cases, some people who have MAP can have colorectal cancer without any polyps, while others have more than 1,000 polyps. The colorectal polyps are often found in people in their 40s.

25. Neurofibromatosis Type 1 - is caused by a mutation in the NF1 gene. People with neurofibromatosis type 1 have patches of skin that have a different color from the rest. The patches of skin are called cafe-au-lait spots that can be smooth or raised and from beige to dark brown. People with neurofibromatosis type 1 also develop neurofibromas along the nerves. Most tumors are benign, but some can become malignant over time. Neurofibromatosis type 1 increases the risk of brain cancer, adrenal gland cancer, rhabdomyosarcoma, neuroblastoma, neuroendocrine tumors, soft tissue sarcoma, and leukemia.

26. PalB2 - carrying the PalB2 gene can dramatically increase a woman's risk of breast cancer. Women carrying the PalB2 gene have a 33% chance of getting breast cancer by age 70: the risk being even higher in women with a family history of breast cancer.157 If a mutation carrier has a strong family history, the risk goes up to 60% by age 70.157 The PalB2 mutation follows behind the BRCA1 and BRCA2 genes as the top genetic risk factor for breast cancer.157 Women who undergo a prophylactic mastectomy may reduce their risk of breast cancer by 90%.91-93

27. Peutz-Jeghers Syndrome - is caused by a mutation in the STK11 (also called LKB1) tumor suppressor gene and causes a large number of polyps to develop in the gastrointestinal tract. It also causes dark spots on the lips, inside the mouth and on other mucous membranes. Peutz-Jeghers syndrome increases the risk of colorectal, stomach, pancreatic, small intestine, and breast cancers. It also increases the risk of bowel obstruction.

28. POT1 - encodes protection of telomeres protein 1 (POT1), which together with other components of the telomere associated protein complex (shelterin), regulates telomerase access to the telomere and suppresses the DNA damage response.330 POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, chronic lymphocytic leukemia (CLL), angiosarcoma (particularly cardiac angiosarcomas), and gliomas.330 Additional cancers (e.g., colorectal cancer, thyroid cancer, breast angiosarcomas) have been reported in individuals with POT1-TPD but with very limited evidence.330 The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of POT1 associated cancers are diagnosed in adulthood.330

29. Rb1 - an altered form of Rb1, retinoblastoma gene, is associated with cancer of the eye in infants, and may increase bladder cancer risks.91 Somatic inactivation of RB contributes to the development of these tumor types as well as prostate, breast, lung, and bladder cancer.

30. Turcot Syndrome - is related to Lynch syndrome and familial adenomatous polyposis (FAP). People with Turcot syndrome develop many polyps in the colon. Turcot syndrome is caused by a mutation in the APC, MLH1 or PMS2 gene. It increases the risk of colorectal cancer and brain cancer.

31. Von Hippel-Lindau Disease (VHL) - is a multi-system disorder characterized by abnormal growth of blood vessels (called hemangioblastomas or angiomas). Hemangioblastomas may develop in the retina, certain areas of the brain, the spinal cord, and other parts of the nervous system. Other types of tumors can develop in the adrenal gland, kidney, and pancreas. Individuals with VHL also have a higher risk to develop certain types of cancer, especially kidney cancer. Nearly all individuals with VHL are found to have mutations in the VHL gene.158

32. Werner Syndrome - causes premature aging that begins during the teenage years. It is caused by a mutation in the WRN gene. People with Werner syndrome have an increased risk of developing bone cancer, melanoma, soft tissue sarcoma and thyroid cancer. Wiskott-Aldrich syndrome - affects blood cells and cells of the immune system. People with

Wiskott-Aldrich syndrome have lower numbers of platelets, which can cause them to bruise and bleed easily. They also have a higher risk for infection because their immune cells don't work properly. Wiskott-Aldrich syndrome increases the risk of leukemia and lymphoma and is caused by mutations in the WAS gene.

33. Xeroderma Pigmentosum (XP) - affects the skin so it can't repair sun damage like it normally would. When someone has XP, their skin is more sensitive to ultraviolet radiation from the sun. People with XP have a high risk of developing melanoma and non-melanoma skin cancers. XP is linked to mutations in several genes including the XPC, ERCC2 and POLH genes.