Genetic Syndromes

Author: Marisa Healy, BSN, RN
Content Contributor: Michael LaRiviere, MD
Last Reviewed: March 10, 2022

What are genes and how do they work?

Genes are made up of DNA and passed down from parents to their children. Some genes act as instructions to make proteins in your body. It is thought that humans have between 20,000 and 25,000 genes.

DNA is like a cookbook, and all cells have the same cookbook. A gene is like a recipe, and the protein that the gene makes instructions for (called coding) is the cooked meal. Different types of cells all have the same DNA but use that DNA to make different types of proteins. For example, liver cells use genes to make proteins to make bile, while neurons in the brain use different genes in the same DNA to make neurotransmitters.

Some genes make proteins that tell cells when to divide and when to stop dividing. These are often the genes that are affected in cancer. In an adult, some cells divide quickly and often, while other cells stop dividing. Skin cells, for example, keep dividing throughout your life. Neurons, on the other hand, stop dividing or divide very slowly.

When a gene that helps with cell division is affected (called a mutation in the DNA), cells may begin to divide even when they shouldn’t. When this mutation causes cells to divide and grow unchecked and out of control, cancer starts to form.

What is a genetic syndrome?

A genetic syndrome is a disease or group of diseases caused by a gene mutation. Genetic mutations may run in families, or they can happen in a person as a new, "de novo" mutation. DNA is inherited (passed down) from both parents, carried on twenty-three chromosomes from each parent, for a total of forty-six chromosomes. Two chromosomes are sex chromosomes, or "allosomes" – XX for women or XY for men. The remaining chromosomes are called "autosomes."

A genetic syndrome with a mutation in the DNA on an autosome is passed on in either an "autosomal dominant" or "autosomal recessive" pattern.

  • An autosomal dominant syndrome needs only one parent's copy of the gene to cause a mutation. This mutated gene is "dominant" over the normal gene.
    • An example of this is the BRCA1 mutation causing breast cancer. If a woman inherited a BRCA1 mutation from her parent, she is at higher risk for breast cancer herself. Because only one copy of the mutated gene is needed, autosomal dominant genetic syndromes often affect many people in the family.
  • On the other hand, an autosomal recessive syndrome requires both parents' DNA to have the mutated gene. If a person inherits the mutated gene from both parents, he/she is at risk of developing the syndrome. Because two copies of the mutated gene must be inherited, autosomal recessive diseases affect fewer members of a given family.

How does a genetic syndrome relate to cancer?

While there are many genetic syndromes, only a few genetic syndromes are linked to higher cancer risk. Most cancers are not related to genetic syndromes. Most cancers happen later in life, after years of DNA damage that mutates genes over time.

Cancer-related genetic syndromes affect an important gene from the beginning of life. These syndromes may then lead to cancer at a much younger age. While many families have members with cancer in old age, families with cancer-related genetic syndromes have a pattern of cancer in children and/or younger adults.

The genes affected in these syndromes tend to play a role in cell division, cell growth, DNA damage recognition, and DNA damage repair. Many of these genes produce "tumor suppressor" proteins, whose normal function is to keep cells from dividing and growing out of control. When tumor suppressor genes are damaged, cells have the chance to divide and grow out of control, possibly forming tumors or cancer.

Genetic Syndromes Related to Cancer

(Table adapted from 1 Weitzel et al.)

Autosomal dominant syndromes

Genetic Syndrome

Hereditary breast and ovarian cancer (HPOC)

  • BRCA1: breast cancer, ovarian cancer.
  • BRCA2: prostate cancer, pancreatic cancer, melanoma.
  • 1 in 400; higher in Ashkenazi Jewish and other ethnicities.

Hereditary prostate cancer

  • HPC1, HPCX, HPC2/ELAC2, PCAP, PCBC, PRCA.
  • Estimated at about 10% of prostate cancers.

Neurofibromatosis 1

  • NF1: neurofibrosarcoma, pheochromocytoma, optic glioma, meningioma.
  • 1 in 3,000-4,000.

(see http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1)

Neurofibromatosis 2

  • NF2: vestibular schwannoma/acoustic neuroma.
  • 1 in 33,000.

(see http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-2)

Tuberous sclerosis

  • TSC1, TSC2: renal cancer, renal angiomyolipomas, myocardial rhabdomyoma, ependymoma, astrocytoma; benign tumors.
  • 1 in 6,000.

(see http://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex)

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

  • MLH1, MSH2, MSH6, PMS2, EPCAM: colorectal cancer, endometrial cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, small bowel cancer, ovarian cancer, renal cancer, ureteral cancer; earlier development of benign colon polyps.
  • 1 in 4,200-7,000 colorectal cancers.
  • Turcot syndrome: glioblastoma.

(see http://ghr.nlm.nih.gov/condition/lynch-syndrome)

Familial adenomatous polyposis (FAP)

  • APC: colorectal cancer, gastric cancer, duodenal cancer, ampullary cancer.
  • 1 in 7,000-22,000.
  • Turcot syndrome: medulloblastoma.

(see http://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis)

Beckwith-Wiedemann syndrome

  • CDKN1C, NSD1: Wilms tumor, hepatoblastoma, adrenal carcinoma, gonadoblastoma.
  • 1 in 10,500-13,700.

(see http://ghr.nlm.nih.gov/condition/beckwith-wiedemann-syndrome)

Peutz-Jeghers syndrome

  • STK11/LKB1: colorectal cancer, small bowel cancer, pancreatic cancer, breast cancer, ovarian cancer.
  • 1 in 25,000-300,000.

(see http://ghr.nlm.nih.gov/condition/peutz-jeghers-syndrome)

Von Hippel-Lindau syndrome

  • VHL: retinal and central nervous system hemangioblastomas, renal cell cancer, pheochromocytoma, endolymphatic sac tumors.
  • 1 in 36,000.

(see http://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome)

Cowden syndrome

  • PTEN, KLLN, SDHB, SDHD (AD): breast cancer, thyroid cancer, endometrial cancer.
  • 1 in 200,000.

(see http://ghr.nlm.nih.gov/condition/cowden-syndrome)

Carney complex

  • PRKAR1A: subcutaneous myxoid tumors, adrenocortical nodular hyperplasia, testicular cancer, atrial myxoma, pituitary adenoma, breast fibroadenomas, thyroid cancer, schwannoma.
  • Fewer than 750 people.

(see http://ghr.nlm.nih.gov/condition/carney-complex)

Li-Fraumeni syndrome

  • p53: breast cancer, sarcomas, brain tumors, adrenocortical carcinoma, leukemia.
  • 1 in 5,000-20,000.

(see http://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome)

Costello syndrome/faciocutaeneoskeletal syndrome

  • HRAS: epithelioma, bladder cancer, rhabdomyosarcoma, vestibular schwannoma/acoustic neuroma.
  • 1 in 300,000-1,250,000; 200-300 people.

(see http://ghr.nlm.nih.gov/condition/costello-syndrome)

Melanoma syndromes

  • p16/CDNK2, CDK4, CMM: malignant melanoma.

Multiple Endocrine Neoplasias (autosomal dominant)

Genetic Syndrome

Multiple Endocrine Neoplasia (MEN) 1

  • MEN1: parathyroid adenoma, pituitary adenoma, pancreatic islet cell tumor, less commonly other tumors.
  • 1 in 30,000.

(for all MEN subtypes, see http://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia)

Multiple Endocrine Neoplasia 2A

  • RET: medullary thyroid cancer, pheochromocytoma, parathyroid adenoma.
  • 1 in 35,000.

Multiple Endocrine Neoplasia 2B
(formerly 3)

  • RET: medullary thyroid cancer, pheochromocytoma, mucosal neuromas.
  • 1,750 people.

Familial Medullary Thyroid Carcinoma
(an MEN2 subtype)

  • Medullary thyroid cancer.

Multiple Endocrine Neoplasia 4

  • CDKN1B: parathyroid adenoma, pituitary adenoma, other tumors.
  • Prevalence unknown, but rare.

Autosomal Recessive Syndromes

Genetic Syndrome

Ataxia-telangiectasia

  • ATM: leukemia, lymphoma.
  • 1 in 40,000-100,000.

(see http://ghr.nlm.nih.gov/condition/ataxia-telangiectasia)

Xeroderma pigmentosum

  • XPA-G, POLH: skin cancers, melanoma, leukemia.
  • 1 in 1,000,000; higher in Japan, North Africa, and the Middle East.

This table shows the most common genetic syndromes related to cancer. The National Institute of Health's Genetics Information page has information about each syndrome mentioned above.

Resources for more information

Learn about genetic counseling and genetic testing.

References

American Cancer Society. (2020). Family cancer syndromes. Retrieved from https://www.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html

American Society of Clinical Oncology (ASCO). (2020). Li-Fraumeni Syndrome. Retrieved from https://www.cancer.net/cancer-types/li-fraumeni-syndrome

Daly, M. B., Pilarski, R., Axilbund, J. E., Berry, M., Buys, S. S., Crawford, B., ... & Klein, C. (2016). Genetic/familial high-risk assessment: breast and ovarian, version 2.2015. Journal of the National Comprehensive Cancer Network, 14(2), 153-162.

Hampel, H., Bennett, R. L., Buchanan, A., Pearlman, R., & Wiesner, G. L. (2015). A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genetics in Medicine, 17(1), 70.

Kresak, J. L., & Walsh, M. (2016). Hereditary Cancer Syndromes in Children: Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis. Journal of pediatric genetics, 5(2), 98.

Mester, J., & Eng, C. (2015). Cowden syndrome: Recognizing and managing a not‐so‐rare hereditary cancer syndrome. Journal of surgical oncology, 111(1), 125-130.

McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nature reviews. Clinical oncology. May 2014;11(5):260-271.

NIH: Genetics Home Reference. https://ghr.nlm.nih.gov/

Vasen, H. F., Tomlinson, I., & Castells, A. (2015). Clinical management of hereditary colorectal cancer syndromes. Nature Reviews Gastroenterology and Hepatology, 12(2), 88.

Weitzel JN, Blazer KR, Macdonald DJ, Culver JO, Offit K. Genetics, genomics, and cancer risk assessment: State of the Art and Future Directions in the Era of Personalized Medicine. CA: a cancer journal for clinicians. Aug 19 2011.

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