Cancer Genetics
by G. Lypas, M.D., Medical Oncologist

Hereditary Cancer Risk

Everyone runs a risk of developing cancer at some point in their life. Unfortunately, this risk is substantially higher for some individuals, who have inherited a mutation (fault) in certain genes. Currently, more than 50 genes or groups of genes have been identified. In most of these cases, there is a strong family history of cancer, meaning that in certain families, a number of members have been diagnosed with cancer, often in ages younger than what is expected for each type of cancer.


What are Genes?

Each one of our cells contains approximately 300,000 genes; each gene controls a specific function or structure in our body, height. Genes are made from a chemical substance, called DNA (DeoxyriboNucleic Acid). For some features, the final outcome may be modified by environmental factors (e.g. skin color is mainly determined by genes; however sun exposure will also affect it). Some genes control significant functions which, if they are not performed appropriately, may lead to cancer. 


Genes and Cancer Risk

In 5-10% of patients with cancer, inherited gene damage (mutation) can be detected, and is the main cause for the development of cancer in these individuals. For example BRCA1 mutation carriers, have an increased lifetime risk of developing breast cancer, which can be as high as 80%. They also have a risk of ovarian cancer, which can be up to 40%, as well an increased risk for a second breast cancer. In individuals with Lynch syndrome carriers, the lifetime risk of developing colon cancer can be as high as 80% and, for uterine cancer, as high as 60-70%.

Another 20% of cancer patients do have a family history of cancer as well; however, it is not possible to detect one of the currently known genetic alterations.

It is still important to keep in mind that most cancers are not hereditary and happen in people with no significant family history; these cancers are called “sporadic”.



Diagnosing an inherited mutation of a cancer susceptibility gene can have very important implications:

  • It allows a healthy individual to take appropriate measures in order to diagnose cancer at an early, probably curable stage or even reduce the risk of developing cancer altogether (e.g. removal of bowel polyps through colonoscopy, which might become cancerous).
  • It informs people who already have had cancer, about potential risks of additional cancer diagnoses. When such information is available upfront in a patient’s treatment, it may also affect treatment decisions e.g. more extensive vs more conservative surgery.

Proper assessment of cancer family history is usually the first essential step. Such an assessment may lead to a diagnosis of an inherited mutation, which increases cancer risk. Family members who are aware of their increased cancer risk can take appropriate preventive measures. A thorough evaluation of family history is also a key part of genetic counseling.


Genetic counseling

Genetic counseling for cancer:

  • Helps understand the relationship among genes, inheritance and cancer development.
  • Enables patients and families to test for such faulty genes, evaluating their personal and family history of cancer, along with other, non-malignant conditions. Such information may come from biopsies, colonoscopies etc., and sometimes from physical examination (e.g. rare skin conditions).
  • Guides patients and their families to select which member is more appropriate to be tested, and which gene or genes to be tested for.
  • Correctly interprets genetic testing results.
  • Helps individuals who carry a mutation to follow an individualized preventive strategy, based on several medical, demographic and social factors.
  • Guides healthy family members through genetic testing, in case some other family member has been diagnosed to carry a cancer predisposing mutation.


Signs and symptoms

Signs that may indicate the existence of inherited cancer predisposition in a family include:

  • Multiple family members with a diagnosis of cancer (breast cancer) or specific combinations of cancer diagnoses (bowel and endometrial cancer)
  • Diagnosis of cancer at an unusually early age (e.g. younger than 40)
  • Combination of cancer or precancerous conditions with unusual body features (e.g. large head circumference and breast cancer, colon cancer and sebaceous gland adenomas)
  • More than one cancer in the same patient, of the same or different types (e.g. breast cancer at 48 and ovarian cancer at 55, or cancer in both kidneys or both breasts etc)
  • Rare types of cancer (e.g. myeloid thyroid cancer, adrenal gland cancer or retinoblastoma, pheochromocytoma etc)


Genetic testing

When inherited cancer predisposition is suspected, a genetic test is recommended. The procedure is very simple for the patient, as it is routinely performed in a blood sample.

A genetic test for hereditary cancer predisposition may have the following results:

  • Positive: a mutation is present, which increases cancer risk. This mutation is called “pathogenic” or “deleterious”
  • Negative: no mutation is found; this gene is normal
  • Variant of uncertain clinical significance: this result is not clearly negative and usually further evaluation may be necessary
  • True negative/true positive: a family member is tested for a specific mutation that is already known to exist in the family (e.g. a sibling) and found to be negative/ positive.

The most commonly diagnosed conditions of increased hereditary cancer risk involve breast cancer, bowel and other cancers of the digestive system, ovarian, uterine and other gynecological cancers etc.

Many more other cancer types may be associated with inherited caner predisposition, although this is a minority: endocrine glands (e.g. thyroid), urinary tract (e.g. kidney, prostate), sarcomas, brain cancers etc.


Prevention strategies

Prevention strategies available nowadays include diagnostic tests which may detect cancer before it causes any symptoms, or before the patient or a physician may become aware of them (e.g. they may feel a breast lump). It has been documented that diagnosing cancer at an early stage can make a difference for a patient, increasing the chances of cure. In some cases, medication may be used to reduce cancer risk (chemoprevention).

Clinical trials evaluate new drugs, targeting cancers which specifically develop due to inherited gene mutations (e.g. PARP inhibitors for ovarian cancer in women with BRCA1/2 mutations).


Most common syndromes

Each one of the hereditary cancer susceptibility syndromes corresponds to a gene or a family of genes. More than 60 syndromes of this type are currently known; the most common ones include:

Hereditary Breast Ovarian Cancer Syndrome (HBOC)

It is caused by a mutation in BRCA1 or BRCA2 genes. Women with such mutations have a very high risk of breast cancer (60-80%), ovarian cancer (20-40%); even women already diagnosed with breast cancer are at increased risk for a new breast cancer.

The age of breast cancer diagnosis tends to be at younger age than usual (30s or 40s). Other cancers are also diagnosed more often in these mutation carriers e.g. pancreatic, prostate, male breast cancer. Risk reduction options involve:

  • Screening starting from a very young age (usually 25) including annual physical examination, mammography and MRI-mammography, transvaginal ultrasound and tumor markers (for ovarian cancer)
  • Preventive surgery to remove ovaries and tubes and preventive surgery to remove both breasts.

Genetic counseling is extremely important, as it helps the carriers become familiar with these options, and select the ones more appropriate for their age, beliefs and values, family status, health status etc.


Lynch Syndrome (Hereditary non-Polyposis Colorectal Cancer syndrome - HNPCC)

Genes associated with these syndrome are MLH1, MSH2, MSH6, PMS2 & EPCAM. Individuals with a mutation in one of these genes have very high risk of getting colorectal cancer (up to 80%), endometrial (uterine) cancer (up to 60%), at ages younger than usual. Other cancers are also diagnosed more frequently in individuals and families with Lynch syndrome, including stomach, ovarian, pancreatic, kidney and urinary tract cancers.


Familial Adenomatous Polyposis (FAP)

FAP is caused by a mutation in the APC gene. Individuals with FAP develop a very large number of polyps, throughout their colon, usually in their teens, which can reach several hundreds by age 40-50. Many polyps can also develop at the stomach and duodenum. The risk of colorectal cancer for individuals with FAP is extremely high, and is often diagnosed before age 40.


Other conditions

Several other, but even rarer relevant conditions (increased susceptibility syndromes) can be diagnosed; they include:


Hereditary Cancer Susceptibility Syndrome

Types of cancer most often diagnosed

Cowden syndrome

Breast, Male breast, non-medullary Thyroid, Endometrium

Hereditary Diccuse Gastric Cancer syndrome

Stomach (gastric), Lobular breast cancer

Li-Fraumeni syndrome

Breast, Colon/rectum, Adrenal cortical, Larynx, Non-Hodgkin lymphoma, Leukemias, Non-Hodgkin lymphoma, Lung cancer, Fibrosarcoma, Rhabdomyosarcoma, Soft tissue sarcoma, Chondrosarcomas, Osteosarcoma, Glioma, Choroid plexus, Neurofibrosarcoma

Hereditary Multiple Melanoma  & Pancreatic Cancer

Pancreas, ACA, Glioma, Melanoma

Multiple endocrine neoplasia type 1

Carcinoid tumor, Small bowel, Adrenal cortical, Pancreas, islet cell, APUDoma, Parathyroid, Acoustic neuroma

Multiple endocrine neoplasia type 2

Paraganglioma, Parathyroid, Pheochromocytoma, medullary Thyroid, non-medullary Thyroid

Neurofibromatosis type 1

Breast, Carcinoid tumor, Paraganglioma, Pheochromocytoma, Wilms tumor, Leukemias, Rhabdomyosarcoma, Acoustic neuroma, Glioma, Medulloblastoma, Meningioma, Neuroblastoma, Ependymomas, Neurofibrosarcoma

Neurofibromatosis type 2

Acoustic neuroma, Glioma, Meningioma, Ependymomas

Hereditary Paraganglioma

Gastrointestinal stroma, Paraganglioma, Pheochromocytoma, Thyroid, non-medullary, Kidney, renal clear cell

Peutz-Jeghers syndrome

Breast, Colon/rectum, Stomach (gastric), Pancreas, ACA, Testicle, Cervix, Endometrium, Ovaries, Lung cancer

Polyposis, MYH-associated

Colon/rectum, Small bowel

Retinoblastoma, hereditary

Retinoblastoma, Lung cancer, Fibrosarcoma, Rhabdomyosarcoma, Soft tissue sarcoma, Chondrosarcomas, Osteosarcoma, Glioma, Pinealblastoma, Melanoma, Sebaceous gland

Tuberous sclerosis complex

Thyroid, non-medullary, Kidney, Wilms tumor, Oncocytoma, Glioma, Ependymomas

Von Hippel-Lindau syndrome

Pancreas, ACA, Pancreas, islet cell, APUDoma, Paraganglioma, Pheochromocytoma, Kidney, renal clear cell, Soft tissue sarcoma, Endolymphatic sac


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