Contemporary Surgery

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, CA

Cancer Genetics Program, USC/Norris Cancer Hospital, Los Angeles, CA

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.

Predisposing factors

Three factors have traditionally determined the categories of inherited syndromes that predispose to colorectal cancer (TABLE 1):

• A large number of adenomatous polyps.

• Few (if any) adenomas.

• Hamartomatous polyps.

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

  Familial adenomatous polyposis

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.

Attenuated FAP

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.

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

  HNPCC

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.

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.

• Tumor-infiltrating lymphocytes.

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

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

First-line screening

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

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).

  Hamartomatous syndromes

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

  Surgical management

Colonic malignancies

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

Extracolonic malignancies

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.

Lynch syndrome

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.

Disclosure

The authors had no affiliations to disclose.

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