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© 2000 American Society for Clinical Oncology
Lynch Syndrome: Genetics, Natural History, Genetic Counseling, and PreventionFrom the Creighton University School of Medicine, Omaha, NE. Address reprint requests to Henry T. Lynch, MD, Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68131; email htlynch{at}creighton.edu ABSTRACT Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). Its natural history has been investigated extensively, so that highly targeted surveillance and management strategies, melded to its natural history, have proven effective in cancer control. Most important is the early age of onset of cancer (approximately 44 years), involving CRC and the several extracolonic cancers that are integral to the syndrome. With respect to CRC, approximately 70% of cases occur proximal to the splenic flexure. Synchronous and metachronous CRCs are extremely common. Full colonoscopy should be initiated when the patient is between the ages of 20 and 25, and because of the accelerated carcinogenesis of CRC, it should be performed every 1 to 2 years. The presence of initial CRC requires subtotal colectomy, given the mentioned increased frequency of metachronous cancer. Options available for germ-line mutation carriers, in addition to cancer screening, include prophylactic colectomy as well as prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The discovery of mismatch repair germ-line mutations (most commonly MSH2 or MLH1) has added significantly to the recognition of this disease as well as to the search for high-risk individuals throughout families who, with genetic counseling, may become candidates for germ-line mutation testing. Clearly, hereditary nonpolyposis colorectal cancer provides an excellent opportunity for learning about the etio-pathogenesis of cancer at the molecular and clinical levels and how this knowledge might ultimately be exploited for cancer control. A search for chemoprevention agents, such as cyclo-oxygenase 2 inhibitors, as well as for putative environmental effects and how they may interact with the genetic component in CRC etiology should abet this entire cancer control process. COLORECTAL CANCER (CRC) is a major public health problem, as evidenced by its high frequency in the United States and other Western industrialized nations. Specifically, it is expected that 93,800 new cases of cancer of the colon and 36,400 new cases of cancer of the rectum will occur in the United States in 2000.1 During this same period, mortality from cancer of the colon is projected to be 47,700, and from cancer of the rectum, 8,600.1 We believe that at least 10% of the entire CRC burden (13,020 new cases and 5,630 deaths) will be the result of a primary genetic susceptibility factor. This estimate of the hereditary burden is likely to be conservative, given the phenomenon of low-penetrant genes, such as the I1307K mutation in the APC gene in familial adenomatous polyposis (FAP), as described by Laken et al.2 In many of these hereditary CRC-prone disorders, inclusive of , hereditary nonpolyposis colorectal cancer (HNPCC) of the Lynch syndrome I and II variants, molecular geneticists have identified culprit germ-line mutations. Molecular genetic findings have enabled hereditary CRC to be divided into the following two groups: (1) tumors that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbor characteristic mutations (such as transforming growth factor beta type II receptor and BAX) and behave indolently, of which HNPCC is an example; and (2) tumors with chromosomal instability, which tend to be left-sided, show aneuploid DNA, harbor characteristic mutations (such as K-ras, APC, and p53), and behave aggressively, of which FAP is an example.3 Our purpose here is to describe HNPCC’s phenotype, genotype, differential diagnosis, natural history, and pathology, with an emphasis on how this information can be used effectively for cancer control. Historically, Warthin identified a cancer-prone family in 1895 and reported it for the first time in 1913.4 A half-century later, Lynch et al5 described two Midwestern kindreds that they characterized as having "cancer family syndrome." Because of the similar array of cancers, inclusive of CRC, the original data from this family, now referred to as family G, were given to Lynch and Krush, who subsequently updated the Warthin family.6 After all these years, mutations in the mismatch repair (MMR) gene, MLH1, have been identified in family G.7 CANCER FAMILY HISTORY Knowledge about hereditary cancer has expanded at a momentous rate during the past two decades, due in a major way to prodigious advances in molecular genetics with the discovery of an increasing variety of cancer-prone germ-line mutations that are etiologic for a variety of hereditary cancer syndromes.8 It is likely that progress in cancer genetics would have been enhanced even further if greater attention had been given to the cancer family history.9,10 Unfortunately, family history of cancer receives short shrift in the overall evaluation of high-risk patients. For example, it is rare to find sufficient family history on a typical medical chart to establish a hereditary cancer syndrome diagnosis should it be present in the family of concern.10 DIFFERENTIAL DIAGNOSIS The extant genetic and phenotypic heterogeneity in CRC leads to the admonition that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Hence, it is necessary to ascertain cancer of all anatomic sites, and even noncancer phenotypic stigmata, such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome, in obtaining a family history.
It is extremely important that the family physician, surgeon, medical oncologist, and/or cancer geneticist diagnostician understand the differential diagnosis of hereditary CRC as depicted in Table 1
EXTRACOLONIC CANCERS The extracolonic carcinomas that occur in Lynch syndrome II include carcinomas of the endometrium, ovary, breast, stomach, small bowel, pancreas, hepatobiliary tract, ureter, renal pelvis, and skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas in the Muir-Torre syndrome).3 With respect to carcinoma of the endometrium, the most common extracolonic cancer of HNPCC among women, Wijnen et al12 have shown that CRC cannot invariably be considered the sine qua non for defining HNPCC in patients with an MSH6 germ-line mutation, given the fact that carcinoma of the endometrium exceeds carcinoma of the colon in women with this germ-line mutation. Carcinoma of the breast has only recently been identified as an integral lesion in HNPCC.13 It is likely that additional cancer and extracancer phenotypic features will one day be identified as integral to this disorder. The extracolonic cancer issue in HNPCC has appropriately led to the expansion of the original Amsterdam criteria.14,15 CANDIDATES FOR MOLECULAR GENETIC TESTING Molecular genetic testing is the most powerful diagnostic tool available for hereditary cancer syndrome diagnosis. Examples of cancers for which there are germ-line tests that are available for patients include FAP (APC mutation), hereditary breast-ovarian cancer syndrome (BRCA1 or BRCA2 mutation), Li-Fraumeni syndrome (p53 mutation), familial atypical multiple mole melanoma syndrome, particularly when associated with pancreatic cancer (p16 mutation), and HNPCC of the Lynch syndrome variants (mutation of an MMR: MSH2, MLH1, PMS1, PMS2, or MSH6), the subject of this article.3 FAMILY INFORMATION SERVICE Once we have a pedigree sufficiently developed, so that we can be reasonably certain that we are dealing with a hereditary cancer syndrome, we begin educating the family members about screening and management programs that are melded to features of the hereditary cancer syndrome’s natural history. Ideally, we do this with a group of family members in a geographic area where the majority reside. This education program is initiated before DNA testing. The patients need to understand the benefits of DNA testing (awareness of the clinical significance of the germ-line mutation, how this mutation determines cancer susceptibility [including its penetrance, when known], and available surveillance and management protocols). They also must be aware of the potential liabilities, which include fear, anxiety, apprehension, potential problems of insurance and employment discrimination, and intrafamily strife. The patients read and discuss our informed consent document, which they sign if they wish to proceed with DNA testing. They are also told that they may elect to abstain from DNA testing and/or withdraw from the clinical and/or research program at any time without penalty. We have conducted more than 100 such family information services during the past several decades and find these to be a cost-effective and highly efficient way of educating and counseling all interested family members from a geographic catchment area during a single setting. These sessions make the best use of the physician’s time and effort, have a group therapy potential, and are welcomed by patients. Family members often state that this is the first time a physician has told them about their cancer risk and what they could do about it. We also prepare a newsletter for periodic distribution and provide anniversary letters indicating need for flexible sigmoidoscopy in FAP and full colonoscopy in the case of the Lynch syndrome, due to the proximal predilection of CRC in that syndrome. Screening for integral extracolonic cancers, particularly endometrial and ovarian carcinomas, is indicated in the Lynch syndrome II variant. MICROSATELLITE INSTABILITY The discovery of MSI16 in CRC and its linkage to HNPCC in 1993 "opened new chapters in tumor biology and in the clinical management of patients with heightened cancer susceptibility."17 MSI is a unique form of genomic instability that embraces a litany of cancer types, some of which are related to HNPCC. A National Cancer Institute workshop17 has created new terminology for MSI. Specifically, tumors are now classified as high-frequency MSI when two or more of a panel of five microsatellite markers demonstrate instability by insertion/deletion mutations; they are classified as low-frequency MSI when only one of the five markers shows instability. High-frequency MSI tumors have been identified in approximately 15% of all sporadic CRCs, which also show a unique clinical and pathologic phenotype that in many ways is characteristic of HNPCC, in contrast to low-frequency MSI and microsatellite-stable tumors. Boland et al17 have stressed the importance of identifying CRC patients showing high-frequency MSI tumors, since a subset will harbor MMR gene mutations and will therefore have a direct impact on the diagnosis and management of the patient and his or her family members. Additionally, the biology of high-frequency MSI tumors differs from that of low-frequency MSI and microsatellite-stable tumors.16 The high-frequency MSI phenotype is associated with a predominance of proximal CRC in concert with those histopathologic and clinical findings that are consonant with HNPCC. There is also an increased frequency of mucinous and signet cell carcinomas, as well as an increase in diploid tumors detected by flow cytometry.3,18 Iino et al19 studied 30 colonic adenomas and 17 hyperplastic colonic polyps from 24 affected HNPCC individuals. DNA was obtained from paraffin-embedded tissue and analyzed for MSI and mutations known to cause MMR deficiency. Most of the adenomas in those patients with a definitive HNPCC diagnosis carried MSI (80%). Of keen interest was a finding of transition from low-frequency MSI to high-frequency MSI which "correlated with the finding of high-grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size." A potential application of MSI testing is in the selection of appropriate chemotherapeutic agents. For example, Carethers et al20 investigated the effect of fluorouracil on MMR-deficient CRC cell lines and found a growth advantage indicative of tolerance to fluorouracil by the MMR-deficient cell lines. It is conceivable that the MSI status could aid in the selection of patients who might benefit from selected chemotherapeutic agents, a hypothesis that merits further testing in a well-controlled clinical trial. MSI in CRC provides the potential for a rational and cost-effective testing process. It also provides statistical data to underscore a bimodal model, in which tumors are either MSI-negative or MSI-positive. Clearly, more research in this area is warranted. The majority of tumors from families that fulfill the Amsterdam criteria are MSI-positive,21,22 a phenomenon that suggests that MMR deficiency underlies most HNPCCs. Paradoxically, when Amsterdam-positive families are tested for mutations in MMR genes (most often MLH1 and MSH2), only between 45% and 86%23-26 show an MMR mutation. In those CRC families who do not fulfill the Amsterdam criteria, the so-called "HNPCC-like" families, the proportion of mutations in MLH1 or MSH2 is still lower (8% to 30%).23,24,27 Considering the sum total of this evidence, Lynch and de la Chapelle3 tentatively propose that "the presence or absence of a germ-line mutation in an MMR gene should be incorporated into the definition of HNPCC. By this criterion, the diagnosis of HNPCC will be missed in some patients because not all MMR genes are studied and because no mutation detection method is perfect." For example, the role of MSH6 in cancer phenotype is not yet fully explored.28 Kolodner et al,29 for example, have reported that MSH6 mutations give rise to an attenuated HNPCC phenotype. In at least two HNPCC or HNPCC-like families, MSH6 mutations were implicated,30,31 and a high proportion of CRC patients with "mild" MSI was recently described as having germ-line mutations of MSH6.32 Wu et al33 studied the relationship between MSI and MMR mutations among 36 patients with suspected HNPCC who were divided equally into low-frequency MSI and high-frequency MSI groups. Findings disclosed that in the low-frequency MSI tumor group, four (22%) of 18 patients carried presumably causative MSH6 mutations. Whether MSH3 or other genes, such as BAX and TGFßRII, will turn out to contribute to inherited predisposition to CRC is not yet clear.34,35 It may take time until the entire mutational spectrum of HNPCC is defined. Lynch and de la Chapelle3 therefore speculate that additional loci will likely be detected that will eventually lead to the identification of further genes, and these mutations will contribute to HNPCC or HNPCC-like syndromes.36 PATHOLOGY Distinctive pathology features of CRC in Lynch syndrome include poorly differentiated tumors, with an increased frequency of mucinous and signet cell carcinomas, as well as tumors with diploid features on flow cytometry. Colonic adenomas are found in approximately 20% of colons of HNPCC patients with CRC. Jass and Stewart37 identified adenomas in the Lynch syndrome as occurring early and being larger and more often villous with more high-grade dysplasia than adenomas in the general population. These findings are consistent with our hypothesis that adenomas in HNPCC have a greater proclivity for malignant degeneration (accelerated carcinogenesis) than sporadic adenomas.3 These HNPCC CRCs also show peritumoral lymphocyte infiltration, Crohn’s-like reaction, and tumor-infiltrating lymphocytes (TILs). SCREENING Järvinen et al38 evaluated the efficacy of CRC colonoscopic screening in a controlled HNPCC trial that extended over 15 years. The CRC incidence and survival rates were compared in two cohorts of at-risk members of 22 HNPCC families. One hundred thirty-three subjects had colonic screening at 3-year intervals, and 119 control subjects (at-risk HNPCC patients who refused screening) had no screening. Results showed CRC to have developed in eight screened subjects (6%) compared with 19 control subjects (16%) (P = .014). The CRC rate was reduced by 62%. In mutation-positive subjects, CRC rates were 18% among screened subjects versus 41% among controls (P = .02). All CRCs in the study group were local, causing no deaths, compared with nine deaths caused by CRC among the controls. The overall death rates were 10 versus 26 subjects in the study and control groups, respectively (P = .003); in mutation-positive subjects, there were four and 12 deaths (P = .05). These authors concluded that CRC screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by approximately 65% in HNPCC families. Nevertheless, CRC in HNPCC may occur despite this intensive surveillance. The aim of a study by Renkonen-Sinisalo et al39 was to determine whether survival was greater among patients whose CRC was discovered through colonoscopic surveillance than those whose CRC was diagnosed by symptoms. Not unexpectedly, the stage at diagnosis was found to be more favorable (P < .001) in the surveillance versus nonsurveillance group. The CRC-specific 10-year survival rate was 93% in the surveillance group, which was significantly better than the 68% seen in the nonsurveillance group (P < .02). The investigators drew the following conclusions: (1) colonoscopic surveillance enables early detection of CRC in HNPCC and reduces CRC mortality; (2) colonoscopy should be performed more frequently, at intervals of only 1 or 2 years, in mutation carriers; and (3) even in relation to optimal colonoscopic surveillance, prophylactic colectomy should be seen as one possible option, at least in cases in which colonoscopy is technically difficult or where poor compliance exists. Clearly, the death rate from CRC can be drastically reduced in the Lynch syndrome through meticulous attention to colonoscopy. It should be initiated when the patient is between the ages of 20 and 25 years and repeated, ideally, every 1 to 2 years. Prevention through colonoscopy is, therefore, melded to HNPCC’s natural history, considering early age of onset, proximal location of CRC, and accelerated carcinogenesis. Surgery for CRC in HNPCC should include subtotal colectomy, because of the excess of synchronous and metachronous CRC,3 and annual endoscopic evaluation of the remaining rectum.40 Accelerated carcinogenesis for CRC in HNPCC is an important consideration, particularly with respect to the need for more frequent colonoscopic screening. For example, it takes approximately 8 to 10 years for a tiny adenoma to evolve to a carcinoma in the general population41; in the case of HNPCC, it is predicted that an adenoma may become a carcinoma in only 2 to 3 years.42 Hence, we recommend that colonoscopy be initiated when the patient is 25 years old (because of the early age of onset of CRC) and repeated every 1 to 2 years.
The case for full colonoscopy screening should be extended to the general population. For example, Lieberman et al43 have shown that colonoscopic screening can detect advanced colonic neoplasms, defined as an adenoma that is Special consideration for the remaining extracolonic cancers includes upper endoscopy in HNPCC families with a history of gastric cancer and/or who reside in high-risk incidence areas, such as Japan and Korea. Screening is not practical at this time for small bowel and hepatobiliary tract cancers. With respect to the upper uroepithelial tract, urine cytology and ultrasound are recommended for evaluation of the ureter and renal pelvis, particularly when these problems are identified in the family. GYNECOLOGIC SCREENING We recommend transvaginal ultrasound and endometrial aspiration with cytology for endometrial cancer screening. These tests should be initiated by the time the patient is 30 years old. In the case of the ovaries, we recommend transvaginal ultrasound and CA-125 screening, both of which should also be initiated by age 30. We repeat these gynecologic screening tests annually. PROPHYLACTIC SURGERY We recommend the option of prophylactic colectomy in obligate gene carriers and, in particular, those patients with poor compliance, those with several colonic adenomas (especially at an early age), and those individuals experiencing poor quality of life because of severe fear, anxiety, and apprehension about succumbing to CRC. Patients who harbor one of the culprit HNPCC germ-line mutations are offered this option as an alternative to lifetime colonoscopic surveillance. Genetic counseling must be provided so that patients can be in a better position to evaluate the advantages as well as the potential sequelae of these varying management strategies. In the case of prophylactic colectomy, the surgical mortality risk is low, but there is a possible long-term morbidity of frequent bowel movements. Patients also need to know that they will require continued endoscopic surveillance of their remaining rectal mucosa, since its cancer risk is approximately 1% per year.40 Why is prophylactic subtotal colectomy considered an important option for these high-CRC-risk HNPCC patients? The answer is predicated on a number of anecdotal reports of interval CRCs occurring within 1 to 4 or 5 years after surveillance colonoscopy. For example, Lanspa et al46 studied 225 individuals with 313 colon cancers from families on file in the Creighton University Lynch syndrome resource. In six of these patients, from different families, CRCs arose within 4.5 years of a normal colonoscopy. Another 17 patients had metachronous colon cancers within 5 years of resection (less than subtotal colectomy) of their initial colon cancer. Thus, of 225 CRC patients from Lynch syndrome families, 10.2% had CRC within 5 years of colonoscopy or colon resection. Prophylactic surgery in the Lynch syndromes raises the question of whether the level of risk in the disorder merits preventive colectomy. DeCosse’s answer is that, "[i]n the added presence of defective HNPCC genes, the answer seems affirmative."47 In the case of Lynch syndrome II, he states that when surgery is planned for the presence of CRC, prophylactic bilateral oophorectomy and hysterectomy, particularly if the woman is postmenopausal, should also be offered as an option. This is a consideration that we have long recommended.48-51 The rationale for prophylactic colectomy in HNPCC does not vary significantly from its well-accepted orthodoxy for cancer control in FAP. For example, in FAP, the average age of CRC onset is approximately 39 years, whereas in HNPCC, it is approximately 40 to 44 years. Importantly, synchronous and metachronous CRCs occur with approximately the same frequency in germ-line carriers of the two syndromes. FAP differs with respect to its phenotype of florid polyposis and a higher penetrance of CRC expression than in HNPCC. The interest in and intent for prophylactic colectomy and/or prophylactic removal of the endometrium and ovaries were evaluated in 347 individuals from 20 HNPCC families who had been tested for mutations in MLH1 or MSH2. Of those evaluated, 144 were positive for such a mutation and 203 were negative. During counseling, before disclosure of their test results, we discussed with patients whether they would consider a prophylactic colectomy or prophylactic gynecologic surgery if found to be mutation-positive. Approximately half of the responders stated that they would consider a prophylactic colectomy if they were found to be positive for an MMR mutation. This response was equal among males and females. Two thirds of the women stated that they would consider prophylactic hysterectomy and bilateral salpingo-oophorectomy if they were found to be positive for an MMR mutation. After genetic counseling with disclosure of results, approximately half of those who were positive said they would consider prophylactic colectomy. In turn, among the women who were positive, approximately half stated that they would consider a prophylactic hysterectomy and bilateral salpingo-oophorectomy (H.T.L., unpublished data). In conclusion, prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy should be considered as options for an obligate gene carrier should the woman have completed her family, show poor compliance, have fear and anxiety, desire the procedure, and/or present with CRC.52,53 FREQUENCY OF HNPCC Many problems are encountered when studying the frequency of HNPCC. Foremost is the classification criteria (Amsterdam criteria being more stringent), the experience of the investigator, geographic differences, decreased gene penetrance, and possible founder effects.3 In the past, to establish the frequency of HNPCC, most investigators determined the proportion of all CRC patients who fulfilled the Amsterdam criteria.14 By this method, estimates varying between approximately 0.5% and 5% were obtained.54-58 Other methods have yielded highly discordant results. For example, Cannon-Albright et al59 suggested that a high proportion of all colorectal tumors were due to heritable mutations. By segregation analyses, Houlston et al60 concluded that 13% of CRC cases fit the model of dominant inheritance, whereas Aaltonen et al,61 studying a consecutive cohort of young CRC patients, extrapolated an HNPCC frequency of only 0.5% to 0.9%. Obviously, when using the Amsterdam or similar criteria as a sole definition, the smaller the family and/or the less pedigree information available, the less likely the definition of HNPCC will be fulfilled. This could skew the results and hamper comparisons between different series. Moreover, the Amsterdam criteria require the cancer to be colorectal in all affected family members, thus ignoring families with key members affected by extracolonic HNPCC cancers, particularly those of the endometrium.33 More "relaxed" pedigree criteria for HNPCC have therefore been proposed.62 NEW CLASSIFICATION OF LYNCH SYNDROME A key issue is how HNPCC should be defined and classified. Tumors from the great majority of Amsterdam criteria–positive families are MSI-positive,21,22 which suggests that MMR deficiency underlies most HNPCC. However, when Amsterdam-positive families are tested for mutations in MMR genes (usually just in MLH1 and MSH2), only between 45% and 86%23-26 show a mutation. In CRC families who do not fulfil the Amsterdam criteria (HNPCC-like families), the proportion with mutations in MLH1 or MSH2 is lower, ie, 8% to 30%.23,24,27 Therefore, phenotypic variation, in concert with differing HNPCC genotypes, such as the MSH6 mutation,12,63 may require reclassification in terms of so-called classical HNPCC. For example, as mentioned previously, women with the MSH6 mutation in putative HNPCC families show a later age of cancer onset and an excess of endometrial carcinoma as opposed to CRC.12 Therefore, such families would be missed should one adhere to the original Amsterdam criteria.14 Given the fact that as many as 40% to 60% of so-called classical HNPCC families do not harbor any of the presently known mutations predisposing to this disorder, one might consider reclassification of some of them should certain features of their cancer phenotypes vary significantly from what is now considered HNPCC. There is the possibility that certain differences in the phenotype of these alleged classical HNPCC families might be due to yet-to-be-identified mutations and/or modifier genes. Thus, newer classification systems might broaden our understanding of HNPCC-like families and assign entirely new diagnostic criteria for CRC-prone syndromes that might not appropriately fit under the rubric of classical HNPCC. This problem might well be comparable to the dilemma of how MSH6 mutation carriers fit, at least at this time, under current terminology inclusive of even the expanded Amsterdam criteria.15 SURVIVAL Increased survival after CRC has been observed in patients with the Lynch syndrome. This phenomenon was first described in the early 1980s.64,65 Sankila et al66 reported survival to be improved for HNPCC in a population-based study of CRC in a province in Finland. Watson et al11 studied survival in 274 cases (98 Lynch syndrome families) and 820 case-consecutive CRC series. Cases had lower-stage disease at diagnosis than the controls, which may have been due to rarer distant metastases at the time of diagnosis. The estimated death rate in HNPCC cases, adjusted for stage and age differences, was, at most, only two thirds that of the controls. Hypotheses to explain this extraordinary finding are as follows: (1) mutator genes, such as MLH1 or MSH2, cause genomic instability, which contributes to an enormous burden of microsatellite disturbance that overwhelms CRC, sending cells to apoptosis; and (2) there is an immune response (peritumoral lymphocytic infiltration, Crohn’s-like reaction, and TILs admixed with tumor cells). We have found a highly statistically significant excess of TILs in HNPCC CRCs when compared with sporadic CRCs. Tumors with high-frequency MSI were found to show a statistically significant correlation with TIL excess in the HNPCC CRCs. We speculate that the findings of the Crohn’s-like reaction, an excess of TILs at the pressing tumor border, and TILs within the CRCs suggest that a peculiar immune response may be driving the biologic behavior of these tumors and thereby contributing to the improved survival that seems to exist in CRCs in HNPCC when compared with sporadic CRCs.11 Once the mechanism(s) is more fully understood, immune intervention in the treatment of HNPCC can be envisioned. This speculation is abetted by the studies of Maxwell-Armstrong et al,67 who tested the ability of 105AD7, an anti-idiotypic monoclonal antibody that mimics the tumor-associated antigen 791Tgp72, to recruit activated lymphocytes to the tumor site. In this study, patients with CRC were immunized with 105AD7 before surgical resection of their tumors. These patients experienced increased expression of the alpha-subunit of the interleukin-2 receptor on TILs, as determined by both immunohistochemistry and flow cytometry. More significantly, vaccinated patients survived three times longer than control patients. Together with previous reports demonstrating increased cytotoxic responses to tumors in 105AD7 recipients, this study suggests that 105AD7 vaccination controls tumor growth by targeting effector T cells to the site of the tumor and perhaps to circulating micrometastases. 105AD7 vaccination may be a prime candidate for use as an immunotherapeutic agent in patients with early disease.
Along this same vein, expression of MICA and MICB, human major histocompatibility complex class I–related molecules, is mainly limited to intestinal epithelium. These molecules are induced by a variety of adverse conditions such as infection or transformation. MICA/MICB are recognized by cytotoxic V HEALTH INSURANCE CONSIDERATIONS Much concern has been given to the potential for insurance discrimination against hereditary cancer at-risk patients. However, what seems to be important is patients’ perceptions—namely that they will be subject to an insurance discrimination penalty—which have posed a deterrent to our own research over the years in both HNPCC and hereditary breast-ovarian cancer. Special legislation (federal and state) is needed to prevent insurance discrimination against patients with a high genetic predisposition to cancer. Compliance with screening in HNPCC will be abetted when insurance coverage is provided to these high-risk patients. Insurance companies will require further research to demonstrate the efficacy of morbidity/mortality reduction through screening and/or prophylactic surgery. Ideally, special cancer prevention clinics will become available for high-risk patients, particularly if insurance coverage is provided. Physician and patient education as well as media (print, television, and radio) attention to the importance of family history and the timely identification of hereditary cancer syndromes, collectively, should improve these cancer prevention objectives. Matloff et al69 examined the decisions cancer genetics specialists (genetic counselors) would pursue personally should they be at 50% risk of harboring a mutation that predisposes to hereditary breast/ovarian cancer syndrome (BRCA1/BRCA2) or HNPCC. One hundred sixty-three (55%) of the 296 individuals queried via questionnaires responded. Eighty-five percent indicated that if they were at 50% risk of carrying a BRCA1/BRCA2 mutation, they would pursue genetic counseling, and if found to be positive for the mutation at age 35, 25% would pursue prophylactic bilateral mastectomies, while 68% would undergo prophylactic oophorectomy. With respect to HNPCC, 91% of respondents would pursue genetic counseling and 17% would elect prophylactic colectomy. Fifty-four percent would elect prophylactic hysterectomy and 52% would elect prophylactic oophorectomy if positive for a mutation. Furthermore, approximately 68% would not bill their insurance companies for genetic testing, because of concern about discrimination, and 26% would use an alias when undergoing DNA testing. Professional psychologic support would be sought by 57% in order to enable them to cope with the results of testing. ADVERSE SELECTION AND LIFE INSURANCE From the perspective of life insurance providers, there is concern about adverse selection, namely, the tendency for high-risk patients to use information, such as knowledge of an MSH2/MLH1 or BRCA1/BRCA2 mutation, without notifying the insurance carrier in order to obtain greater levels of insurance protection (per unit cost) than if no information asymmetry existed.70 We are not aware of the extent of adverse selection in HNPCC. However, Zick et al,70 in their analysis of women who tested positive for the BRCA1 germ-line mutation, found that, albeit surprisingly, they did not exploit this informational advantage through purchasing more life insurance when compared with women who had not undergone genetic testing. However, as we have noted anecdotally,71 HNPCC family members who are at risk and/or positive for the germ-line mutation have told us that they plan to buy, or already have bought, more life insurance because of this asymmetry. GENETIC COUNSELING Genetic counseling is mandated when dealing with a hereditary cancer syndrome, particularly when consideration is given to DNA studies. For example, the American Society of Clinical Oncology recommends that genetic testing for cancer susceptibility be used only when there is a strong family history of cancer, the test can be adequately interpreted, the results will influence management of patient and family members, and the laboratory used is committed to the validation of testing methodologies.72 Available options for maximizing cancer control must be addressed, including prophylactic surgery. Patients must be advised that the prediction of cancer risk will be limited in germ-line mutation carriers only by the penetrance of the gene. In the case of the Lynch syndrome, the likelihood that a germ-line mutation carrier will develop CRC is 80% to 85% during that individual’s lifetime. However, it is not possible to distinguish which individuals will develop cancer as a result of reduced penetrance of the culprit mutation. Genetic counseling should include a compassionate counselor who is knowledgeable about hereditary cancer and who has an empathetic "listening" ear. Counseling should be performed before and after germ-line testing, and confidentiality protection should be secure. The perception of insurance and employment discrimination must be addressed. CHEMOPREVENTION Surgical resection remains the only curative treatment for CRC, for any patient in the general population or in any genetic risk category, wherein cure is possible commensurate with detection at an early pathologic stage. However, chemoprevention provides new hope for reduction of morbidity and mortality. What is needed, however, is a better understanding of the mechanisms of carcinogenesis, where normal cells and tissues become malignant. New approaches to synthesizing and testing new (and often novel) drugs to prevent cancer (chemoprevention) in contrast with classical chemotherapy must be provided.73 Chemoprevention, however, remains a research issue. Tamoxifen provides a gold standard as a model for chemoprevention in hereditary cancer, given its high rate of success in high-risk breast cancer patients. Available chemoprevention candidate agents for CRC in HNPCC include nonsteroidal anti-inflammatory drugs, such as aspirin, sulindac, and cyclo-oxygenase 2 inhibitors. We can learn about chemoprevention through evidence of adenoma reduction with cyclo-oxygenase 2 inhibitors in the case of FAP.74 However, there are no data on the proven efficacy of chemoprevention products in HNPCC. Therefore, randomized case-control studies are needed to determine the efficacy of these putative chemopreventive agents, since chemoprevention is still in the early stages of development. Carefully designed clinical studies are required to validate specific pharmacologic agents for chemoprevention and to assure safety and efficacy. New and better agents need to be developed. We also need broad-based educational efforts that stress compliance with the goals of chemoprevention.73 High-risk patients need to understand that it is appropriate to treat "healthy" people with preventive agents. Patients also need to know that the absence of clinical symptoms may not guarantee that one is healthy. We need to adhere to the dictum "primun non nocere" (first do no harm). Benefits and risks of chemoprevention strategies need to be understood by patients and their physicians so that appropriate consideration can be given toward the utilization of these agents. INCREASED ATTENTION WORLDWIDE TO HNPCC Given the public health importance of hereditary cancer in general and, in particular, the fact that the most common hereditary syndrome involving CRC is the Lynch syndrome, it is important that clinicians obtain a sufficiently detailed cancer family history in order to identify these families. They must then integrate the cardinal features of the Lynch syndrome, as part of the family history, so that this disorder can be diagnosed at a timely period, wherein cancer control can be properly exercised through highly targeted surveillance and management strategies. Given the evidence from Järvinen et al38 on the screening benefit and from Vasen et al75 on the cost-effectiveness of screening, it is evident that many lives can be saved through such cancer control measures. The literature on HNPCC has advanced at a veritably logarithmic rate since the report by Lynch et al in the mid-1960s.5 It has been particularly embellished by reports of the MSH2 and MLH1 MMR mutation discoveries.3 An excellent example of increased identification of HNPCC families has taken place in Uruguay and Argentina. Specifically, the Creighton team visited Montevideo, Uruguay, in the mid-1990s to study an HNPCC family originally described by Sarroca in 1977.76 This family was observed during several trips by the team to Uruguay, with the ultimate discovery of an MLH1 germ-line mutation, which was found to segregate in the family in accordance with its expected autosomal dominant mode of genetic transmission.77 As a result of these visits, interest in HNPCC increased remarkably in that country. More than 60 HNPCC families have since been identified in Uruguay, and they now constitute an invaluable HNPCC registry. Similarly, involvement of the Creighton team, in collaboration with Carlos Vaccaro, MD, a colorectal surgeon from Buenos Aires, Argentina, has led to the identification of HNPCC families with MMR germ-line mutations; a registry has been developed over a span of several years in Argentina which now contains more than 50 HNPCC families. Clearly, this has led to an extremely positive impact on the colorectal surgery, gastroenterology, medical oncology, and general physician communities in Uruguay and Argentina and, consequently, to the identification of an enormous number of HNPCC families. In conclusion, although the genetic etiology of the Lynch syndrome has been stressed throughout this article, one must nevertheless consider the impact of environmental effects on its etiology. Lichtenstein et al,78 in a Scandinavian study involving 44,788 pairs of twins, assessed the risks of cancer at selected sites for twins of persons with cancer. Findings disclosed that inherited genetic factors make only a minor contribution to cancer susceptibility in most types of neoplasms. Hence, environmental effects are exceedingly important in the etiology of sporadic cancer. These authors note that "[t]he relatively large effect of heritability in cancer at a few sites (such as prostate and colorectal cancer) suggests major gaps in our knowledge of the genetics of cancer." We believe that the effects of primary genetic factors on cancer, such as age of cancer onset, susceptibility to multiple primary cancers, reduced penetrance, and even survivability, may be influenced heavily by environmental effects, including lifestyle.
ACKNOWLEDGMENTS Supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services and by National Institutes of Health grant no. RFA 1U01 CA86389. Kristen Drescher, PhD, assisted on special sections of this article. NOTES The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. REFERENCES 1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50: 7-33, 2000[Abstract] 2. Laken SJ, Petersen GM, Gruber SB, et al: Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 17: 79-83, 1997[Medline]
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