Cancer Genetics

Cancer Genetics is the study of the contribution of genetics to an individual’s risk for cancer.  Approximately one in three people will develop cancer in their lifetime.  Many factors can influence a person’s risk for developing cancer, such as:

  • Age
  • Tobacco use
  • Obesity
  • Nutrition
  • Chemicals
  • Radiation
  • Infectious organisms
  • Genetics 

Some of these risk factors can be modified through lifestyle, but some factors cannot be changed.

Approximately 5-10% of all cancers are caused by inherited gene mutations that predispose people to develop cancer. These gene mutations can be passed down through the generations. Knowledge of family history is very important.

Characteristics of a family history that increase the chances of hereditary cancer are:

  • Cancer at an early age,
  • The same cancer occurring in many family members,
  • Many cancers occurring in one person, and/or 
  • Breast or ovarian cancer in the context of Ashkenazi (Eastern European) Jewish ancestry.

There are genetic tests available for some cancers that can explain if personal and/or family history is due to an inherited gene mutation.  If a person has a gene mutation related to cancer predisposition, they are at an increased risk for developing cancer and should undergo increased cancer surveillance.  If a person has a normal gene test result, their risk for cancer may lessen but they may still be at an increased risk. 

We have more than 20,000 genes and it is possible that the specific gene causing your family history of cancer has not been discovered.  In this case, people with a normal gene test result may still need to have increased monitoring.  It is important that a board-certified genetics specialist provide a hereditary cancer risk assessment before genetic testing and interpret the results of the genetic test.

Statistics - American Cancer Society

Hereditary Breast Cancer

One in eight women (12.5%) will develop breast cancer in their lifetime.  Several genes have been discovered that when mutated or changed can increase a person’s risk of breast cancer. 

The BRCA1 and BRCA2 genes account for more than half of hereditary breast cancer.  Other genes, including p53, PTEN, CHEK2, ATM, and other undiscovered genes are also involved in hereditary breast cancer.  A gene mutation can increase a person’s risk for different types of cancers. 

While the BRCA genes are most known for their breast cancer risk, they also increase the risk for:

  • Ovarian
  • Prostate
  • Pancreatic cancer

TP53 gene mutations cause a condition called Li-Fraumeni Syndrome and are associated with an increased risk of a variety of cancers including:

  • Sarcoma
  • Breast
  • Brain
  • Leukemia
  • Adrenal gland cancers

A PTEN gene mutation causes Cowden Syndrome. It is associated with abnormal skin growths as well as benign (non-cancerous) and malignant (cancerous) tumors of the:

  • Thyroid
  • Breast
  • Uterus

There are many screening tools available to detect breast cancer at an early stage.  It is recommended that people at increased risk for breast cancer have mammogram surveillance as well as breast imaging Magnetic Resonance Imaging (MRI).

Indications for a genetics evaluation for hereditary breast cancer include:

A personal history of:

  • Breast cancer before the age of 50 or ovarian cancer at any age,
  • Bilateral breast cancer or two or more primary cancers of the breast,
  • Breast and ovarian cancer in the same individual, and/or
  • Breast cancer in a male.

A maternal or paternal family history of:

  • Two or more people in the family with breast and/or ovarian cancer,
  • One or more close male relatives with breast cancer,
  • Early onset breast or ovarian cancer (before age 50) in a close relative, and/or
  • Confirmed genetic mutation in a relative.

* People who belong to certain ethnic groups, such as those of Ashkenazi Jewish descent, are more likely to have a BRCA gene mutation. Some individuals may be appropriate candidates for genetic testing. This is true even if they do not have significant personal or family history of breast and/or ovarian cancer.

Hereditary Colon Cancer

The lifetime risk for developing colorectal cancer is about 1 in 19 (5.4%).   Many factors can increase a person’s risk for developing colon cancer and can include: 

  • Age
  • Diet
  • Obesity
  • Physical inactivity
  • Smoking
  • Alcohol
  • History of Ulcerative Colitis or Crohn’s disease
  • Family history 

Approximately 5% of people with colon cancer have an inherited susceptibility to the disease. 

Two genetic conditions that can increase a person’s risk for colon cancer are Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colon Cancer (HNPCC). 

FAP is caused by mutations in the APC and MYH genes.  It causes a person to develop many, often thousands, of polyps in their colon.  A polyp is a mushroom-like growth in the colon that can be cancerous.  If left untreated a person with FAP has about a 100% chance of developing colon cancer.

HNPCC is also often called Lynch syndrome.  Lynch syndrome is caused by mutations in several genes, including MLH1MSH2, MSH6, and PMS2.  Individuals with Lynch Syndrome do not develop as many polyps as in FAP, but they still have an increased risk of colon cancer.  Lynch syndrome also increases a person’s risk of uterine, ovarian, stomach, and other cancers. 

Colonoscopy is a screening tool to detect and remove polyps in the colon.  People at increased risk for colon cancer must have colonoscopies more often to screen for colon cancer.

Indications for a Genetic Evaluation 

A personal or family history of:

  • Colon cancer before the age of 45
  • Pre-cancerous polyps before the age of 40
  • More than 20 pre-cancerous polyps
  • Uterine cancer before the age of 45
  • Three or more people in the family with colon, uterine, stomach, or ovarian cancer
  • Confirmed genetic mutation in a relative
  • Genetics of Colon Cancer

Von Hippel Lindau Syndrome

Von Hippel Lindau Syndrome (VHL) is a genetic (inherited) condition. VHL predisposes an individual who has this condition to a variety of tumors.  The most common tumors seen in VHL include:

  • Hemangioblastomas of the retina/brain/spine
  • Pheochromocytoma tumors of the adrenal gland
  • Kidney cancer of the clear cell type

It is important to promptly diagnose VHL. Most tumors associated with VHL are benign (non-cancerous). Benign tumors can still cause serious problems.  For example, a hemangioblastoma is a benign tumor involving blood vessels. Retinal hemangioblastomas can cause vision loss and even blindness.  Pheochromocytomas (pheo) are also typically benign but can cause uncontrollable high blood pressure. 

Other tumors include

  • Endolymphatic sac tumors of the inner ear
  • Benign kidney and pancreatic cysts
  • Benign tumors of the reproductive tract 

VHL is caused by mutations in the VHL gene. If a parent has VHL then each of their children has a 50% chance of also having VHL.

Additional information.

Multiple Endocrine Neoplasia Type 1 (MEN1)

MEN1 is a condition that causes a person to develop tumors in their endocrine glands. This primarily involves the parathyroid, pancreas, and pituitary gland, as well as other characteristic tumors.  MEN1 is caused by a mutation in the MEN1 gene.

Parathyroid Tumors

The most common tumors to develop in MEN1 are those involving the parathyroid glands. Nearly 100% of people with MEN1 will develop parathyroid tumors in some or all the parathyroid glands by the age of 50 years. These tumors are typically benign (not cancerous) and may cause health problems because of the excessive hormones they produce. Parathyroid tumors produce increased amounts of parathyroid hormone, causing hyperparathyroidism. Excess parathyroid hormone causes calcium to leave the bones and go into the blood. Elevated levels of calcium in the blood are called hypercalcemia. 

This can cause:

  • Bone weakness (osteoporosis)
  • Kidney stone formation
  • Fatigue

Pancreatic Tumors

People with MEN1 can also develop tumors in the pancreas.  Pancreatic tumors in MEN1 are named after the hormone they produce. Gastrinoma and insulinoma tumors are the most common.  A gastrinoma produces excess gastrin and can cause ulcers, reflux, and diarrhea.  These symptoms are called Zollinger-Ellison syndrome (ZES).  Gastrinomas can also occur in the duodenum and can be malignant (cancerous).  An insulinoma produces excess insulin and causes hypoglycemia (low blood sugar).  Insulinomas are almost always benign.

Pituitary Tumors

The pituitary tumors found in MEN1 are also named after the hormone they produce, with prolactinoma being the most common.  A prolactinoma produces excess prolactin.  It can cause menstrual irregularity in women and reduced libido in men.  Pituitary tumors can cause other symptoms such as headache and changes in vision, by pressing on nearby structures in the brain.  Pituitary tumors in MEN1 are typically benign. 

Other Tumors in MEN1

Less often, people with MEN1 will develop carcinoid or adrenocortical tumors.  Carcinoid tumors occur in the thymus gland or lung and can be malignant.  Adrenocortical tumors occur in the adrenal gland and are typically benign.  Non-endocrine, benign tumors may also develop, such as facial angiofibromas, collagenomas, and lipomas.

Summary of Cancer Risks in MEN1

In MEN1, the highest risks for cancer are tumors in the pancreas, duodenum, and carcinoid tumors.

*MEN1 should not be confused with a condition called MEN2.  While MEN1 and MEN2 are similar in that they both predispose people to develop tumors of the endocrine glands, they are two completely different conditions.

Multiple Endocrine Neoplasia Type 2 (MEN2) & Medullary Thyroid Cancer

MEN2 is a condition that causes a person to develop tumors in their endocrine glands, including the thyroid, parathyroid, and adrenal glands. 

People with MEN2 are at risk of developing a specific type of thyroid cancer called medullary thyroid cancer.  The age of onset varies and may occur in young children.

In MEN2, the tumors that develop in the adrenal and parathyroid glands are typically benign (not cancerous) but can cause serious health problems because of the excessive hormones they produce.  Tumors can develop in the adrenal gland called pheochromocytoma (pheo).  These tumors produce excessive amounts of hormones called catecholamines (such as adrenaline), which can cause a person to have very high blood pressure.

People with MEN2 can also develop tumors in the parathyroid glands that produce excessive amounts of parathyroid hormone.  This is called hyperparathyroidism.  Excess parathyroid hormone causes calcium to leave the bones and go into the blood.  Elevated levels of calcium in the blood are called hypercalcemia.  This can cause the bones to become weak (osteoporosis) and kidney stones to develop.

25% of all people diagnosed with medullary thyroid cancer have the hereditary form caused by mutations in the RET gene.  Most of these people have a family history of medullary thyroid cancer, but sometimes they do not.

Types of MEN2

MEN2 is classified into types based on the family history and the specific RET gene mutation identified: MEN2A and MEN2B. Familial Medullary Thyroid Cancer (FMTC) is grouped with MEN2 because it is also caused by RET gene mutations. MEN2A is the most common type of MEN2. There is a very high risk of medullary thyroid cancer in MEN2A. The typical age of onset is in young adulthood. About 50% of people with MEN2A will develop a pheochromocytoma and about 25% will develop hyperparathyroidism.

MEN2B is the most aggressive form of MEN2. It causes medullary thyroid cancer to develop in early childhood. About 50% of people with MEN2B will develop a pheochromocytoma. Hyperparathyroidism is uncommon. Individuals with MEN2B can also develop:

  • Benign nodules on their lips and tongue
  • Abnormalities of the gastrointestinal tract
  • Taller stature than expected in comparison to their family members

FMTC occurs when there is a family history of medullary thyroid cancer and no other characteristics of MEN2 in the family. The onset of medullary thyroid cancer is typically in middle age.

*MEN2 should not be confused with a condition called MEN1. While MEN1 and MEN2 are similar in that they both predispose people to develop tumors of the endocrine glands, they are two completely different conditions.

Additional information.


Retinoblastoma is a tumor of the developing retina (part of the inner eye) that occurs in children.  Most of these tumors occur before the age of five and many are present at birth.  Tumors can be unilateral (present in only one eye) or bilateral (present in both eyes).  Approximately 60% of patients have unilateral retinoblastoma and 40% have bilateral retinoblastoma.

Retinoblastoma is caused by mutations in the RB1 gene.  The mutation often occurs after birth (usually presents as unilateral in these cases) but is sometimes hereditary (often presents as bilateral in these cases).  

In hereditary retinoblastoma, RB1 gene mutations are either “passed down” from a parent or occur early in the development of the child.  If a parent has hereditary retinoblastoma then each of their children has a 50% chance of inheriting the same gene mutation and developing retinoblastoma.  If it is not hereditary, the risk to future generations is quite low. 

Besides eye tumors, children with hereditary retinoblastoma are at increased risk for other types of cancer or tumors. These include rare tumors of the pineal gland (a gland found in the brain), and cancers of bone, soft tissue, and skin.  Radiation exposure greatly increases the risk of developing secondary tumors.   It is important to identify children at risk for retinoblastoma and other tumors as early as possible to prevent damage.

Genetic testing of the RB1 gene is available with about 80% of mutations in the RB1 gene detected.  A negative genetic test result does not rule out hereditary retinoblastoma, as some mutations are not currently detectable. 

Patients with bilateral retinoblastoma are assumed to have the hereditary form of this condition, although finding the specific mutation is not always possible.  10-17% of patients with unilateral retinoblastoma also have the hereditary form.  If a mutation is identified in a person, it is important to determine if other family members are at risk. 

Early testing and recognition of people at high risk for retinoblastoma may allow for timely intervention and improved outcomes.  Using a variety of current treatments, preservation of sight in retinoblastoma patients is now possible.

Additional information.