Genetics and Hereditary Cancers

Hereditary Colon Cancer: Guide for Health Pros

Approximately 5 to 10 percent of colon cancer is hereditary. The major hereditary colon cancer syndromes are Lynch syndrome (previously known as Hereditary Non-Polyposis Colorectal Cancer or HNPCC) and Familial Adenomatous Polyposis (FAP). Other genes have also been implicated in hereditary colon cancer risk.

The genetic risk assessment service at UT Southwestern Simmons Comprehensive Cancer Center offers testing and genetic counseling for colon cancer and all other identified cancers. Based on an individual’s personal and family history of cancer, our genetic counselors can identify the level of risk, determine if genetic testing is appropriate, and provide guidance for an early detection and prevention strategy.

Watch a video about hereditary colon cancer management.

Colon Cancer Facts

One in 18 individuals (5.5 percent) will develop colon cancer in their lifetime. Of all colon cancer cases, only about 5 to 10 percent are hereditary, linked to gene mutations inherited from one’s mother or father.

Multiple genes are associated with hereditary colon cancer, but mutations in genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) are the most common cause of the hereditary form of the disease. Prediction models can estimate an individual’s risk for a Lynch syndrome mutation.

Additional information on colon cancer predisposition genes can be found on the Hereditary Colon Cancer Gene List listed below.

Approximately 25 to 35 percent of colon cancer is familial, meaning the disease occurs more often in family members than can be expected in the general population even though a particular gene mutation has not been identified in the family. With familial colon cancer, the specific cause of colon cancer is unknown but likely due to combinations of risk factors including genetics, lifestyle, and environment that increase risk in the family.

Screening recommendations vary for individuals with an increased lifetime risk for colon cancer based on a hereditary cancer syndrome or family history.

The remainder of colon cancer diagnoses (around 70 percent) are considered random or sporadic and non-hereditary, without a known etiology. Risk factors for sporadic colon cancer include: 

  • Age (9 out of 10 people are over age 50)
  • Inflammatory bowel disease, ulcerative colitis, Crohn’s disease
  • Diets high in fat and/or low in fiber
  • Smoking/tobacco use 
  • Physical inactivity and/or obesity
  • Type 2 diabetes

Genes

Cowden Syndrome

Gene
PTEN

Component Cancers
Breast, uterine, thyroid, colon, and renal cancers

Of Note
Associated with macrocephaly; colon polyps (hamartomatous); skin finding such as acral keratosis, facial trichilemmomas, and oral papillomatous papules; autism; lipomas; fibrocystic breast disease; thyroid nodules; and uterine fibroids.

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Familial Adenomatous Polyposis (FAP)

Gene

APC

Component Cancers
Colorectal, small bowel, gastric, pancreatic, thyroid, hepatoblastoma, and CNS tumors

Of Note
Individuals with FAP develop hundreds to thousands of colorectal polyps beginning at age 16 on average. Colon cancer risk is essentially 100 percent without intervention. Attenuated FAP (AFAP) is a less severe phenotype.

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Hereditary Diffuse Gastric Cancer

Gene
CDH1

Component Cancers
Diffuse gastric cancer and lobular breast cancer

Of Note
Gastric cancer incidence varies widely by geographic regions. Patient’s origin should be considered when evaluating CDH1 criteria.

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Juvenile Polyposis Syndrome (JPS)

Gene
BMPR1A and SMAD4

Component Cancers
GI juvenile-type hamartomatous polyps (stomach, small intestine, colon, and rectum); colon, stomach, upper GI, and pancreatic cancers

Of Note
SMAD4 mutations are also associated with hereditary hemorrhagic telangiectasia (HHT).

Lynch Syndrome

Gene
MLH1, MSH2, MSH6, PMS2, EPCAM

Component Cancers
Colorectal, uterine, ovarian, gastric, small bowel, pancreatic, CNS tumors, bladder/ureter cancer, hepatobiliary, and renal cancers

Of Note
Lifetime cancer risks are based on which gene has the mutation; MLH1 and MSH2 have the highest cancer risks. Tumor testing and germline genetic testing are used to identify individuals and families with Lynch syndrome.

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Moderate Risk Cancer Gene

Gene
CHEK2

Component Cancers
Breast, colon, prostate and possibly ovarian, thyroid, and renal cancers

Of Note
1100delC mutation is the most common CHEK2 mutation in Northern European populations.

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MYH Associated Polyposis (MAP)

Gene
MUTYH

Component Cancers
Colorectal, small bowel, and gastric cancers

Of Note
MAP is a recessively inherited cancer syndrome; two MUTYH gene mutations cause MAP. Individuals with one MUTYH mutation may have a slightly increased risk for cancer but the risk is not established at this time (approximately 1-2 percent of the population has one MUTYH mutation).

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Newer Polyposis Genes

Gene
POLD1, POLE, GREM1

Component Cancers
Colorectal cancer and adenomas

Of Note
Phenotype of POL gene mutations may resemble Lynch-like families. Founder mutation in GREM1 identified in Ashkenazi Jewish population.

Peutz-Jeghers Syndrome

Gene
STK11

Component Cancers
Small bowel, colon, stomach, pancreatic, breast, cervical, ovarian sex cord tumors (SCTATs), and sertoli cell tumors

Of Note
Classic pigmentation of lips and buccal mucosa, typically seen PJ-type hamartomatous polyps.

Management of High-Risk Patients

The National Comprehensive Cancer Network (NCCN) has established and published guidelines for cancer care that are focused on quality, effectiveness, and efficiency. The guidelines are continuously updated to reflect current research. Specific recommendations for screening and management of individuals with an increased lifetime risk of cancer due to hereditary colon cancer syndromes are briefly summarized below. Please note that most current and detailed guidelines are available through NCCN “Genetic/Familial High-Risk Assessment: Colorectal.”

NCCN recommendations for high-risk colon cancer genes, including genes implicated in Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) and polyposis genes (APC, MUTYH), have been established (NCCN v1.2015).

For Lynch syndrome, the surveillance guidelines do vary based on the gene in question:

  • MLH1/MSH2/EPCAM mutation carriers are advised to start colonoscopy every 1 to 2 years starting at age 20 to 25, women are recommended to consider prophylactic TAHBSO after childbearing (typically age 35 to 40), and upper endoscopy can be considered every 3 to 5 years starting at age 35 based on family history or in Asian populations due to their elevated gastric cancer risk.
  • For MSH6/PMS2 mutation carriers, colonoscopy is advised starting at age 25 to 30 every 1 to 2 years, prophylactic hysterectomy should be considered after age 40, and other cancer screening can be considered based on family history (these are thought to be lower than MLH1/MSH2 risks).
  • For APC, colonoscopy or flexible sigmoidoscopy is recommended annually starting age 10 to 15 until polyp burden is too great to clear effectively (at this point, total colectomy recommended); upper endoscopy starting at age 20 to 25 to evaluate stomach and duodenum; annual thyroid exam starting in the late teens; desmoid risk warrants annual abdominal palpation with possible imaging if needed.
  • For MUTYH, annual colonoscopy starting by age 21 or based on family history (if polyp burden too great to clear with colonoscopy, colectomy can be considered) with baseline upper endoscopy by age 35.
  • Other high-risk genes related to colon cancer include Peutz-Jeghers syndrome, juvenile polyposis, serrated polyposis syndrome, Li-Fraumeni syndrome and Cowden syndrome (PTEN Hamartoma Tumor syndrome).

NCCN also publishes colon cancer screening recommendations based on increased risk due to family history (Colorectal Cancer Screening v1.2015). Recommendations are based on number of first- or second-degree relatives diagnosed with colon cancer and ages at diagnosis. A first-degree relative with an advanced adenoma is also a consideration for altered colonoscopy screening recommendations. Individuals at an increased risk should discuss this information with their physicians to establish an appropriate screening routine.

Prediction Models for Hereditary Colon Cancer Risk

At Simmons Comprehensive Cancer Center, we use a variety of assessment tools designed to predict an individual’s likelihood of Lynch syndrome (LS). Statistical models have not been developed to predict risk for other hereditary colon cancer syndromes at this time. Not all tools can be appropriately applied to all patients. Each tool is most effective when the patient’s characteristics and family history are similar to those of the study population on which the tool was based. All have limitations, and the risk estimates derived from the tools may differ for an individual patient.

MMRPRO

This tool is available within the CancerGene risk assessment software that also harbors the BRCAPRO model. It utilizes personal/family history of colon and/or endometrial cancer within first- and second-degree relatives, ancestry, location of the colon cancer, age of onset, age of unaffected family members, results of MSI/IHC testing of colon tumor (MLH1, MSH2, MSH6 only) and LS-related mutation carrier status to determine LS-related mutation risk in MLH1, MSH2, and MSH6 only. MMPRO has a few important limitations to keep in mind. Mutation risk calculation does not include LS-related cancers outside of colon and endometrium, MSI in sporadic setting (i.e., BRAF and MLH1 hypermethylation testing of tumor), nor colorectal adenomas/polyps or prophylactic hysterectomy (TAH). Additionally, risk of a PMS2 gene mutation is not calculated with this model.

Myriad Prevalence Tables

Another tool utilized commonly that is also in CancerGene software is the Myriad Prevalence Tables. It is not technically a model of LS mutation risk, but a compilation of data placed in a categorical table from Myriad Genetics’ sequencing of MLH1/MSH2 genes. The information to be gathered from this data is only for likelihood of MLH1 and MSH2 mutation (MSH6 and PMS2 not included). Data is based on the proband with a history of cancer and includes first- and second-degree relatives with colon/endometrial cancer, as well as extra-colonic cancers associated with LS. An important limitation is possible sample bias that may not be representative of general population being tested. Also, the calculations were based on what was recorded on test requisition form, which could possibly be erroneous or incomplete.

PREMM1,2,6 Model

This model predicts likelihood for MLH1/MSH2/MSH6 mutations in an affected proband. The risk calculation is based on the proband’s personal history of a LS-related cancer (colon, endometrial or extra-colonic), age at diagnosis, and gender. Family history considerations in this model include first- or second-degree relatives with LS-related cancers and ages at diagnosis. An important limitation is the exclusion of MSH6 rearrangement and PMS2 mutation data in the study cohort from which this data is based. It also does not take family size or unaffected individuals into account and does not incorporate MSI/IHC data or history of adenomas.

MMR Predict Model

This model utilizes age at diagnosis of colon cancer, multiple primary colon cancers (synchronous/metachronous), family history of colon/endometrial cancer in first-degree relatives only and presence or absence of endometrial cancer. Of note, this model was validated in a Scottish cohort of affected individuals diagnosed before age 55, so it is unclear if this model performs as well in older populations or other ethnicities.