Basic concepts for genetic testing in common hereditary colorectal cancer syndromes

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<ul><li><p>Basic Concepts for Genetic Testing in Common Hereditary Colorectal </p><p>Cancer SyndromesKristina Markey, MS, Lisen Axel, MS, and Dennis Ahnen, MD</p><p>AddressDenver Department of Veterans Affairs Medical Center and University of Colorado Hospital Hereditary Cancer Clinic, 1055 Clermont Street, Denver, CO 80220, USA. E-mail: Dennis.Ahnen@uchsc.eduCurrent Gastroenterology Reports 2002, 4:404413Current Science Inc. ISSN 1522-8037Copyright 2002 by Current Science Inc.</p><p>IntroductionThe last decade has brought compelling advances in theunderstanding of how genetic predisposition leads to dis-ease. This understanding has greatly facilitated the identifi-cation of families with hereditary cancer. This articleidentifies the cardinal features of hereditary cancer syn-dromes and highlights the complex nature of genetic test-ing. To illustrate these concepts, the usual strategy forgenetic testing and result interpretation for the two mostcommon forms of hereditary cancerhereditary nonpoly-posis colorectal cancer (HNPCC) and familial adenoma-</p><p>attempt to review the medical management of these syn-dromes or detail the genotypephenotype correlations;rather, it offers a practical background for the practitionerwho is involved with cancer risk assessment.</p><p>Hereditary CancerIt is estimated that about 5% to 10% of all cancers arecaused by a germline single gene mutation. Such suscepti-bility mutations are inherited in an autosomal dominantfashion, so that each offspring (male or female) of a muta-tion carrier has a 50% chance of inheriting that cancer sus-ceptibility. Thus, most individuals with hereditary canceralso have affected relatives in multiple generations, but thisis not always the case, because of small family size, variablepenetrance, and the possibility that new mutations canoccur in these genes. The highly penetrant cancer suscepti-bility mutations cause an increased risk for cancer at ayoung age and multiple primary cancers, sometimes in theform of synchronous tumors. If a practitioner is able to rec-ognize the clues of hereditary cancer susceptibility from apatients personal and family history, subsequent modifi-cations to the patients cancer screening and treatment reg-imen can have lifesaving potential for the patient and at-risk relatives.</p><p>The patients personal history of cancer and a carefullyperformed family history of cancer are the cornerstones offamilial cancer risk assessment. For patients with coloncancer, information about age at diagnosis, location, his-tology, and stage, as well as history of concurrent or previ-ous colonic adenomas and all other cancers in the family,should be routinely obtained. Some practitioners havefound that a family history screening worksheet is helpfulin this process. For those with a suspicious family history, amore detailed pedigree can be obtained that includesinformation on all close relatives. For all relatives it isimportant to ask about whether they have had any cancer,the cancer type, ages at cancer diagnosis, current age, his-tory of chronic diseases that predispose to cancer (particu-larly Crohns disease and ulcerative colitis for colon cancerrisk), potential occupational and environmental expo-sures, age at and cause of death, and ethnic background.</p><p>Approximately 5% of colorectal cancers are associated with one of the autosomal dominant hereditary cancer syndromes. The two most common familial colon cancer syndromes are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). The causative mutation can be identified in many families with these syndromes by genetic testing of an affected individual. If an affected individual tests positive for a disease-causing mutation, genetic testing of unaffected, at-risk family members can be performed to determine whether they have inherited the cancer-susceptibility mutation, and a personalized cancer surveillance strategy can be devised. Genetic testing significantly enhances cancer risk assess-ment in these families. However, the complicated nature of result interpretation and the emotional impact of the result necessitate that testing be carried out in conjunction with patient education and informed consent by a physician who has a keen appreciation for the inherent challenges. This article describes the genetic testing strategy in HNPCC and FAP.tous polyposis (FAP)is outlined. This article does not Other screening points that can be helpful for colon cancer</p></li><li><p>Genetic Testing in Colorectal Cancer Markey et al. 405</p><p>families include unusual skin lesions or freckling, lumpsor bumps (such as fibromas, lipomas, cysts, or keratoses),and dental abnormalities. It is also important to notewhich pieces of the history are limited or unknown.</p><p>Although an accurate family history is critical to theassessment of familial cancer risk, it is important to under-stand the limitations of self-reported family history. Stud-ies have documented that the details of the cancer-focusedfamily history are not usually all-inclusive and sometimesinclude erroneous information [1]. Often the details ofcancer diagnosis are unknown, incomplete, or misunder-stood. For these reasons, confirming critical cases in thepedigree through review of pathology records is often nec-essary for accurate assessment of the family history.</p><p>The family history information can be assembled intoa pedigree to assess the likelihood of a familial cancersyndrome. The questions asked about the pedigreeinclude the following: Is there an autosomal dominantpattern of cancer in the family? Do the types of cancer fitinto a known cancer syndrome? Do the cancers in thefamily occur at an unusually young age? Is there anyonewith a bilateral cancer or multiple primary cancers? Arethere any rare cancers in the family? Are there several rela-tives who have the same type of cancer? An evaluation ofthe ages at death can provide important informationabout unaffected relatives, because sometimes deathoccurs before the age that cancer would have become evi-dent. In addition to defining family risk, family historycan also be the only way to identify unaffected familymembers who need special cancer surveillance.</p><p>Prior to the availability of genetic testing, the diagnosisof a hereditary cancer syndrome in a family would bemade on the basis of established clinical criteria alone (asdescribed for HNPCC and FAP in the following sections),and all at-risk relatives would be advised to have increasedscreening and surveillance for the development of cancer.However, not all close relatives have a high risk for cancer.Each first-degree relative of an affected individual has a50% risk of having inherited the cancer susceptibilitymutation, so there is an equal chance that the mutationwas not inherited and the general population cancer sur-veillance would be adequate. Genetic testing allows clini-cians to identify the 50% of at-risk family members whohave inherited the disease-causing gene so that they can bescreened appropriately without excessive screening ofunaffected family members. When a cancer susceptibilitymutation is identified for a family, predictive genetic test-ing for unaffected relatives can be done inexpensively, withclose to 100% accuracy. Because many cancer-prone fami-lies do not meet the strict criteria for a clinical diagnosis ofa cancer-susceptibility syndrome, genetic testing, if posi-tive, can clarify whether a genetic syndrome is present andidentify the cancer risks. It is important to note, however,that some families that meet the clinical criteria of a famil-ial cancer syndrome may not have a detectable genetic</p><p>by mutations in other undiscovered genes or because thecurrent testing method is not able to detect the type ofmutation that is present. Nonetheless, in families with anidentified mutation, genetic testing can define cancer riskand allow for a personal cancer surveillance program to betargeted to gene carriers within the family.</p><p>Several medical organizations have offered guidelinesthat support genetic testing for cancer risk. Some of theseinclude the American Gastroenterological Association [2],American Society of Clinical Oncology [3], American Col-lege of Medical Genetics [4], and American Society ofHuman Genetics [4]. Within the statements of thesegroups, the following concepts are stressed: First, pretestgenetic counseling and written informed consent shouldproceed genetic testing. Second, an affected individualshould be the first in the family to be tested, whenever pos-sible. Third, genetic testing should be restricted to appro-priate families (those that have a substantial pretestprobability of having a germline mutation) and used onlywhen the results will alter clinical management. Also, thetesting should be initiated at the age when specialized can-cer screening would begin. Finally, the practitioner must beable to interpret the results adequately, given the clinicalscenario. Genetic testing offers many benefits, but becauseof the inherent challenges, it should be facilitated andinterpreted by well-informed practitioners.</p><p>Informed consentInformed consent is essential for genetic testing, and theissues surrounding gene testing can be quite complex. TheAmerican Society of Clinical Oncology has identified somecritical elements to be discussed in conjunction with writ-ten informed consent for genetic testing [3]. First, informa-tion should be provided about the specific test beingperformed, and the implications of a positive, a negative,and an uninformative result should be discussed. Second,education about the mode of inheritance and the optionsand limitations of medical surveillance and screening fol-lowing testing should be provided. Third, the risks ofgenetic testing should be discussed, including risk of psy-chological distress, risk of insurance and employment dis-crimination, and patient confidentiality. Fourth, thetechnical accuracy of the test and the cost of genetic coun-seling and genetic testing should be explained. Also ofnote, the patient should understand that risk assessmentcan occur without genetic testing and that DNA banking isanother possibility for future testing. In addition to manyof these points, the Cancer Genetics Studies Consortiumemphasizes that practitioners should assist patients inexploring their related personal values and facilitate shareddecision making about genetic testing [5].</p><p>Genetic counselingNot all practitioners have the time or the experience toprovide adequate risk assessment and genetic counseling.mutation, either because their cancer syndrome is caused Specialized programs have been developed to provide</p></li><li><p>406 Large Intestine</p><p>comprehensive services in cancer genetics, and many canbe located at If such a center is not located within areasonable vicinity, a referral to a genetic counselor shouldbe considered. Genetic counselors are Masters-degree-levelgraduates with special expertise in medical genetics and thepsychosocial and ethical elements of genetic disease; theycan act as physician extenders. Many cancer genetic coun-selors are available nationwide and can be easily identifiedat</p><p>Hereditary nonpolyposis colorectal cancerHereditary nonpolyposis colorectal cancer, formerlycalled Lynch syndrome, is the most common hereditarycolorectal cancer syndrome. Early evidence suggestedthat 5% to 8% of all colon cancers could be caused byHNPCC [6], but the actual frequency appears to be lessthan 5%. HNPCC is an autosomal dominantly inheritedsyndrome associated with a high risk of colorectal,endometrial, and selected other cancers. The colon can-cers in HNPCC tend to occur at a younger age, are morecommonly proximal, and are more commonly multiplethan sporadic colorectal cancers.</p><p>The clinical diagnosis of HNPCC is usually made onthe basis of a set of clinical criteria such as the Amsterdamor Bethesda criteria (Table 1) and appropriate genetic test-ing. The syndrome should be considered in individualswith a personal or family history of colorectal cancers thatoccur at an early age, have a proximal location in thecolon, and are multiple, and if there is an autosomal dom-inant pattern of cancer inheritance in the family. The pres-ence of endometrial cancer in the family is another clue tothe diagnosis of HNPCC. The mean age of diagnosis of col-orectal cancer is around 45 years in HNPCC comparedwith about 67 years for sporadic colorectal cancers. Abouttwo thirds of cases of colon cancer in HNPCC occur proxi-mal to the splenic flexure, whereas half to two thirds ofsporadic colorectal cancers are distal to the splenic flexure.About 35% to 50% of patients with HNPCC have synchro-nous or metachronous colorectal cancers, whereas the rateis less than 10% in patients with sporadic colorectal can-cers. By the age of 70 years, individuals with HNPCC have a70% to 82% risk for colorectal cancer and a 42% to 60%risk for endometrial cancer [79]. New germline mutationscausing HNPCC are rare, so that almost all patients withHNPCC will have a suggestive family history if the familysize is not too small.</p><p>Extracolonic cancer is an integral part of HNPCC. Inaddition to the very high risk of endometrial cancer inwomen with HNPCC, an increased risk of ovarian, stom-ach, urinary tract, and biliary tract cancers has beenobserved in HNPCC families. The cumulative risk for theseother HNPCC cancers ranges from around 10% to around20% [10,11]. The association between familial colon cancerand brain tumors has been classified historically as Turcot</p><p>FAP. Genetic studies of families with clinical Turcot syn-drome, however, have identified families with HNPCC andbrain tumors (mostly glioblastomas) and other familieswith FAP and brain tumors (mostly cerebellar medullo-blastomas). Muir-Torre syndrome includes the typicalHNPCC features as well as sebaceous gland tumors(benign and malignant) and keratoacanthomas.</p><p>The histologic features of colon cancers may provideuseful clues to the diagnosis of HNPCC in some families.Usually, HNPCC colon tumors are poorly differentiatedand grow in a solid pattern, showing abundant mucin pro-duction caused by the presence of signet ring cells. Tumorinfiltrating lymphocytes, similar to those seen in Crohnsdisease, have also been reported. Evidence so far has not</p><p>Table 1. Criteria for diagnosis and genetic testing in HNPCC</p><p>Amsterdam IAll of the following must be met</p><p>3 relatives with colorectal cancer involving at least2 generations, 1 a first-degree relative of the </p><p>other 2 and1 colorectal cancer diagnosed before age 50</p><p>FAP should be excludedAmsterdam II</p><p>All of the following must be met3 relatives with an HNPCC-associated tumor (CRC, </p><p>endometrial, small bowel, ureter, or renal pelvis) involving at least</p><p>2 generations, 1 a first-degree relative of the other 2 and 1 or more cases diagnosed before age 50</p><p>Bethesda FAP should be excludedAny one of the following is sufficient to fulfill criteriaAny one of the first three is referred to as modified </p><p>B...</p></li></ul>


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