How genetics can aid the surgical management of hereditary CRC
Director, GenRisk Adult Genetics Program, Medical Genetics Institute, Cedars Sinai Medical Center, Assistant Professor of Medicine, Geffen School of Medicine at UCLA, Los Angeles, CATali
Cancer Genetics Program, USC/Norris Cancer Hospital, Los Angeles, CA
In colorectal cancer, the patient’s DNA may dictate treatments and the need for genetic counseling.
The stepwise progression of colorectal cancer, from aberrant crypt or hyperplasia to adenomatous polyp and then carcinoma, has made it possible to predict genetic mutations.1 Authors have linked the molecular mechanisms involved in the predisposition to colorectal cancer to both hereditary and sporadic tumor formation.
A causative, high-penetrant genetic alteration has been identifiable in 5%– 10% of colon cancers. More than 20% of patients with colorectal cancer or adenomatous polyps have had a first-degree relative with the same.2 Although proportional to familial and heredity breast cancers, colorectal cancer referrals have been underrepresented in our center and cancer genetics clinics in the United States.3
Technical complexities in testing the patient at risk for colorectal cancer may make it more problematic for the gastroenterologist and colorectal surgeon to identify the risk. This article explores the guidelines for identifying, referring, and managing hereditary colon cancers.
FIGURE 1: Classic finding
The presence of adenomatous polyposis is a key determinant in a patient’s genetic predisposition to colorectal cancer. (Illustration by Molly Borman)
Three factors have traditionally determined the categories of inherited syndromes that predispose to colorectal cancer (TABLE 1):419
However, findings that have since blurred these broad classifications are:
Families that meet the criteria for hereditary nonpolyposis colon cancer but in whom no mutation is found.
Individuals with APC gene mutations that have very few adenomas.
A fast-growing number of lowpenetrant genes, which account for some of the attributable risk in familial cases.
Genes associated with colon cancer syndromes
|Adenomatous polyposis syndromes
• Familial adenomatous polyposis (FAP)
• Attenuated familial adenomatous polyposis (AFAP)
• MYH-associated polyposis (MAP)
|Hamartomatous polyposis syndromes
• Peutz-Jeghers syndrome
• Juvenile polyposis syndrome
• Cowden syndrome
SMAD4, BMPR1A, ENG
|Hereditary nonpolyposis colorectal cancer (HNPCC)
||MLH1, MSH2, MSH6, PMS2
|Familial colorectal cancer Type X
|Low-penetrant predisposition to CRC
Familial adenomatous polyposis
Diagnosis of a hereditary cancer syndrome is important to determine multi-organ cancer screening and prophylactic measures, and to prevent or find cancers in their earliest stages.
Classic familial adenomatous polyposis (FAP) is a rare autosomal dominant disease. It has been associated with the development of hundreds to thousands of colorectal polyps and associated cancers (TABLE 2). Though FAP only accounts for about 1% of colorectal cancers, it confers a lifetime risk of 100% without colectomy.4 The striking presentation of hundreds of polyps makes testing straightforward.
FAP lifetime cancer risks5
Mutations in the APC gene give rise to variable colonic and extracolonic risks depending on the location of mutation within the gene (FIGURE 2). Mutations between codons 1301 and 2011 are associated with a sixfold increase in desmoid tumors relative to the low-risk region. Codons 1250–1464 are associated with severe polyposis and earlier onset cancer. Duodenal adenoma risk and extracolonic manifestations are highest between codons 976 and 1067.
FIGURE 2: Phenotype/genotype correlations on the APC gene
Mutations on the 3’ and 5’ ends of the gene and in the alternatively spliced region of exon 9 are associated with attenuated familial adenomatous polyposis. Extracolonic manifestations can occur with mutations present anywhere on the gene, but are more common with mutations in the highlighted areas.
Genetic testing cannot identify all mutations, and individuals without an identified mutation may still be at high risk. Clinical evaluation can determine the need for heightened surveillance.
Mutations that cause attenuated disease are located at the 5’ and 3’ ends of the large APC gene.4 Attenuated familial adenomatous polyposis (AFAP) differs from classic FAP because the former has:
Far fewer colonic adenomas.
A tendency toward proximal and diminutive adenomas that routine colonoscopy may miss.
Later ages of onset for both adenomas and colorectal cancer.6
A convoluted diagnostic path
AFAP poses a particular challenge in diagnosis and management. Gastroenterologists frequently encounter the middle-aged patient with 10–15 or more adenomas but lacks profuse (more than 100) polyposis. A family history of colon cancer or polyps is possible but not necessary.420
Especially suggestive of AFAP is a high adenoma burden in the right colon. Indigo carmine or narrow-band imaging may aid in detecting tiny adenomas. Upper endoscopy demonstrating fundic-gland polyps suggests an APC mutation and can help in the differential diagnosis of polyposis.6
The prevalence of AFAP is unknown. Authors have used the presence of 20 or more synchronous polyps as a guideline for AFAP testing.
However, to further convolute strategies, AFAP mutations have been confirmed in 79-year-old subjects with as few as two adenomas,7 and a few examples of mismatch repair gene mutations with high polyp burden have been reported.
A family history of polyposis/colorectal cancer has been identified in 74% of cases.6 In the remaining cases, FAP occurs either de novo, due to non-paternity or adoption, or other mutations. The mutation detection rate is about 80% for classic FAP and only 60% for the attenuated form—even lower if the diagnosis is less clear.
MYH gene mutations
Inherited mutations in the MYH gene provide a second genetic predisposition to colorectal polyposis and cancer.8 MYH-associated polyposis (MAP) is less severe and classified as “attenuated,” but can have significant polyposis.
MAP is an autosomal recessive condition with biallelic mutations. Two common founder mutations have been identified among European Caucasians.
However, sufficient data are lacking on the risk of mutations in other ethnic populations, or the yield of full sequencing if testing reveals one or no common mutations. Authors disagree over a codominant effect in which one mutation alone could confer increased risk for adenomas.9
Clinical practice guidelines for individuals with HNPCC and familial polyposis syndromes are available at www.nccn.org.
Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome, accounting for 2%–4% of all colon cases. It is due to mutations in a family of genes known as mismatch repair (MMR), which correct errors in DNA replication.421
Colon cancer in the absence of marked polyposis or physical examination findings is characteristic.6 Other cancers occur in HNPCC kindred (TABLE 3).
HNPCC lifetime cancer risks10
HNPCC diagnosis is not as straightforward as FAP because the range of cancers is more diverse, the penetrance is lower, and age of onset is variable. HNPCC cancers do have these common clinical histopathology features:
Predominance of tumors proximal to the splenic flexure.
Crohn-like reaction, mucin, and signet ring cells.
Right-sided location, synchronous and metachronous tumors, and young age of onset are strong predictors of a mismatch repair mutation. The Amsterdam and Bethesda guidelines aid in identifying the patient at risk for HNPCC (TABLE 4).
Guidelines for diagnosis of colorectal cancer
Modified Amsterdam Criteria11
Patient with CRC under age 50.
Patient with 2 HNPCC-associated tumors,*† any age.
Patient with CRC under age 60 with MSI-high histology.
Patient with CRC and one or more first-degree relatives with an HNPCC-related tumor,† one under age 50.
Patient with CRC and two or more first- or second-degree relatives with HNPCC-related tumors,*† any age.
Microsatellite instability tumor testing
Besides the frequent differences in their histopathologic appearance, HNPCC tumors can display a molecular signature known as high-frequency microsatellite instability (MSI-H). This molecular phenotype arises from the underlying germline mutation in any of multiple genes involved in DNA “proofreading,” or mismatch repair.
Mismatch repair causes the increased mutation rate and subsequent cancer risks in HNPCC, and the size variability in the non-coding regions of short repetitive DNA known as microsatellites.13 Immunohistochemical stains are 90%–95% sensitive for detecting microsatellite instability compared with polymerase chain reaction (PCR)-based analysis.
Loss of protein expression for any of the mismatch-repair genes indicates a genetic defect, but does not differentiate somatic from germline mutations. Immunohistochemistry and PCR-based tests for microsatellite instability correlate well. However, in fewer than 3% of cases germline mutations may produce a detectable protein product and yet still cause MSI.14
Genetic discrimination is not currently a problem, so it is not necessary for patients to be tested anonymously.
Immunohistochemical evaluation has gained favor as a first-line screening tool for mutations thanks to the ready availability of antibodies to proteins associated with MMR genes.
Lack of staining for MSH2 is a strong indicator for either an MSH2 or MSH6 mutation. Loss of protein staining for MLH1 can be due either to a germline (inherited) mutation or somatic (sporadic) methylation of the promoter region of MLH1.15
Familial colon cancer Type X
The patient with a family history that meets Amsterdam criteria but with a tumor negative for microsatellite instability may have familial colon cancer Type X, a syndrome distinct from HNPCC. The underlying genetic mechanisms for Type X seem to be heterogeneous.
Type X is as common as HNPCC, but with a lower colorectal cancer risk and a later age of onset. The extracolonic malignancy risk, such as endometrial cancer, is not elevated in Type X.16
Guidelines for nonpolyposis colorectal cancer
The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer developed these guidelines for evaluating the patient for colorectal cancer risk:12
Optimal approach is microsatellite instability (MSI) testing or immunohistochemistry of tumors followed by germline MLH1/ MSH2/MSH6/PMS2 testing in the patient with MSI-H tumors or loss of protein expression.
After a mutation is identified, at-risk relatives should be referred for genetic counseling and testing.
If tissue testing is not feasible, proceed to germline analysis if the patient meets testing criteria.
If no mismatch repair-gene mutation is found in a proband with an MSI-H tumor or a clinical history of HNPCC, the genetic test result is uninformative. Patient and relatives need to be counseled as if confirmed for HNPCC and undergo high-risk surveillance.
If clinical criteria are met but tumor is not MSI-H and no mutation is detected, screening can focus on the colon, but not extracolonic risk.
Assure the patient of confidentiality and current legislation to allay fears related to discrimination based on genetic status.
The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer has created guidelines for evaluating patients (BOX).12 We have developed an algorithm for hereditary colon cancer evaluation and testing based on the number of polyps and tumor characteristics (FIGURE 3).
FIGURE 3: Algorithm for suggested referrals for hereditary CRC testing
Intestinal hamartomas are frequent in Peutz-Jehgers syndrome, juvenile polyposis, and Cowden disease. All these syndromes are autosomal dominant and rare. Characteristic clinical stigmata range from perioral pigmentation, facial trichileomoma, oral papillomas, goiter, and in the case of Cowden disease, esophageal glycogenic acanthosis.
A single juvenile polyp is a common cause of bleeding in childhood, but consider juvenile polyposis when 5 or more polyps are present.
The histopathology of all of these hamartomas are distinct and require expert pathologic review. The colon cancer risks are 10% for Cowden disease, 30% for Peutz-Jehgers syndrome, and 60% for juvenile polyposis syndrome.13
Prophylactic colectomy has been shown to increase survival by decades in familial adenomatous polyposis.2 For polyposis of the rectum, the treatment of choice has been either abdominal colectomy with an ileorectal anastamosis or a restorative proctocolectomy with an ileal pouch and anastamosis. Authors have recommended the latter in patients with:
Florid polyposis, including rectal polyps that cannot be controlled endoscopically.
A history of desmoid tumors.
APC mutations associated with increased rectal cancer risk.6
The patient undergoing ileal pouch and anastamosis can develop pouch adenomas, so continued surveillance with capsule endoscopy or double-balloon enteroscopy is mandatory. Some surgeons have questioned the pouch as the procedure of choice when an alternative exists, but the ileal pouch procedure remains the gold standard.
In AFAP and MAP, laparoscopic-assisted colectomy is the treatment of choice because it usually spares the rectum and allows the remaining mucosa to be readily surveyed.5,11
Because the patient with FAP is at risk for fundic-gland and small-bowel polyps, regular upper endoscopy is indicated. However, no randomized trials have yet determined how frequently a patient should have imaging, if capsule or balloon enteroscopy is more effective, or when to operate.
The need for an operation depends on the location and stage of adenomas. Options range from local resection or ampullectomy for isolated lesions to Whipple procedures. Pancreas-preserving duodenectomy is gaining favor in FAP.
Desmoid tumors are a significant surgical challenge. They can recur and cause major adhesions. Recent data provided an algorithm for surgical versus medical intervention for intra-abdominal desmoid tumors, and reported a higher rate of complete resection than other series.17
Hepatoblastoma is a risk in childhood, so screening should continue until age 5. Thyroid carcinoma also tends to occur early, so authors recommend regular screening through adolescence and early adulthood.
In Lynch syndrome, evaluation for HNPCC should precede an operation. If HNPCC is confirmed, a subtotal colectomy is an option rather than segmental resection. Although no outcome data have compared an ileorectal anastomosis and segmental colectomy in HNPCC, mathematical models have suggested an advantage for the more radical procedure.18
In Lynch syndrome, abdominal colectomy is indicated in the patient with colon cancer who has MMR repair mutations, or the young patient who meets Amsterdam or Bethesda criteria but has no mutation.
An annual colonoscopy is recommended in the patient who has undergone a segmental resection or in the carrier without cancer. If the patient develops high-grade adenomas or cannot undergo adequate imaging, prophylactic surgery is an option.19
Extracolonic cancer in Lynch
The most common malignancy in Lynch syndrome other than colon cancer is endometrial cancer, which may be the presenting cancer in women (TABLE 3). Guidelines include regular transvaginal ultrasound with consideration of endometrial biopsy and CA-125 levels after age 25, and prophylactic hysterectomy/oophorectomy after childbirth to manage both the endometrial and ovarian cancer risks. Upper endoscopy and evaluation for urinary cancer is part of standard screening, but does not mandate any prophylactic intervention.423
Parameters for genetic testing consent20
The American Cancer Society has developed these practice parameters for identifying and testing patients at risk for dominantly inherited colorectal cancer:
Implications of a positive and negative test.
Possibility of an uninformative test.
Options for risk estimation without genetic testing.
Options and limitations of medical surveillance and screening following testing.
Risk of passing mutation on to children.
Technical accuracy of test.
Risk of psychological distress.
Confidentiality and discrimination issues (including knowledge of current anti-discrimination state and federal legislation).—OKG, TG
The authors had no affiliations to disclose.
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