Clinical Translation of Molecular Genetic Knowledge
Ramaswamy has expressed extreme optimism regarding the current diagnosis and treatment of cancer, translating our increased comprehension of the human genome and advances in molecular technology into improvements in the individual patient's diagnosis and management. This molecular revolution may lead to a sea change from population-based risk assessment and empiric treatment to that of a more highly predictive individualized model based on molecular diagnosis and targeted cancer treatment. Predictably, such a personalized approach will not only increase the efficacy of treatment, but it should also decrease toxicity and cost.
This knowledge has recently been applied by Lossos et al through the study of gene expression signatures, which were used to predict the prognosis in patients with diffuse large B-cell lymphoma, wherein six genes were found to be sufficient to predict overall survival. This approach has also led to research showing that fluorouracil(Drug information on fluorouracil) (5-FU), while proven advantageous to the treatment of CRC in general, may not be appropriate in Lynch syndrome patients with CRC tumors showing high-frequency microsatellite instability.[34,35]
Studies have strongly supported the hypothesis that CRCs with high-frequency microsatellite instability may be more immunogenic than microsatellite stable tumors. This finding has been ascribed to the increased numbers of activated cytotoxic lymphocytes in CRC tissues.
Founder Mutations and the Lynch Syndrome
Founder mutation studies have many advantages compared to genetic testing in unrelated populations. For example, founder mutations enable more efficient identification of relatives who are at increased hereditary cancer risk and who thereby can benefit from genetic counseling in concert with highly targeted surveillance and management.
With respect to the Lynch syndrome, there have been at least five examples of founder mutations. In the Finns, one germ-line MLH1 mutation has been found to account for as many as half of all Lynch syndrome cases, while another was found to account for 15% to 20%. Other founder mutations in the Lynch syndrome include an MSH2 germ-line mutation first detected in a large kindred in Newfoundland,[ 38] subsequently found to be widespread in that population through a founder effect. Interestingly, this mutation has been seen in many other populations as well, and actually arises de novo with appreciable frequency.[40,41] Thus, this mutation is a recurrent one worldwide, but its spread in Newfoundland is by the founder mechanism. A mutation of MLH1 is widespread in the Valais region of Switzerland, and a recently identified mutation in MSH2 may account for as many as one-third of all Lynch syndrome cases in the Ashkenazi Jewish population.
Lynch et al have described another example of the founder mutation phenomenon. This instance involves a mutation-namely MSH2 del 1-6-in nine families that have been tracked from their "founder" in Germany in the 18th century through their migrations to and within the United States until the present day.
Practical Diagnostic Strategies
Criteria and Guidelines
Several different sets of criteria and guidelines have been developed in the hope of resolving some of Lynch syndrome's diagnostic pitfalls. The most commonly used-the Amsterdam I and Amsterdam II criteria, and the Bethesda guidelines-are shown in Table 2.[46-48]
For diagnostic purposes, one may also consider so-called "pattern recognition" of the cancer phenotype in probands and their immediate firstand second-degree relatives. Thus, the presence of a striking phenotype such as proximal CRC occurring before age 40, possibly metachronous CRC, mucoid features with signet cell pathology, or the early onset of one or more colonic adenomas, even in only a single first- or second-degree relative, should prompt further investigation of the possibility of Lynch syndrome, even though the findings may fail to qualify for the Amsterdam Criteria or Bethesda Guidelines (Table 2).
The presence in even one relative in a pedigree showing early age of CRC onset, and/or one or more key extracolonic cancer types, should raise a high index of suspicion for a Lynch syndrome diagnosis. This is clearly illustrated by the pedigree shown in Figure 2, which reveals multiple primary cancer and extracolonic cancer types that constitute the Lynch syndrome. Noteworthy in this pedigree is the presence of patients with the Muir-Torre syndrome variant of the Lynch syndrome (sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in concert with visceral cancer).
Microsatellite instability testing of the CRC tissue block should be made and, if positive, one should then search for a germ-line mutation in a mismatch repair gene.[7,8,50] Finally, given the relatively high frequency of CRC in the general population, certain HNPCC-like families may be attributed to chance alone, or there may be cancer phenotypes (such as those attributable to the MSH6 mutation) that constitute an atypical or more benign form of HNPCC.[24,51]
Cancer Control in Lynch Syndrome
Cancer-related morbidity and mortality may be reduced significantly through highly targeted surveillance measures that are based on knowledge of the natural history and cardinal features of the Lynch syndrome (Table 1). Particularly important is full colonoscopy (due to the syndrome's predilection toward proximal CRC), initiated at the age of 25 years (due to early onset of CRC) and repeated annually (due to accelerated carcinogenesis). In women, endometrial aspiration biopsy and transvaginal ultrasound are important, given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer-control strategies have a strong impact on family members at risk once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.
Järvinen and colleagues demonstrated the benefit of colonoscopic screening in HNPCC through a controlled clinical trial extending over 15 years. The incidence of CRC was compared in two cohorts of at-risk members of 22 HNPCC families. CRC developed in 8 screened subjects (6%), compared with 19 unscreened controls (16%; P = .014). The CRC rate was reduced by 62% in those who were screened. All CRCs in the screened group were local, causing no deaths, compared with nine deaths caused by CRC in the controls. The researchers concluded that CRC screening at 3- year intervals reduces the risk of CRC by more than half, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families. The relatively high incidence of CRC even in the screened subjects (albeit without deaths) argues for shorter screening intervals (eg, 1 year). Indeed, Vasen and colleagues discovered five cancers in Lynch syndrome patients within a 3½-year interval following a normal colonoscopy.
Subtotal colectomy as a prophylactic measure among HNPCC patients remains controversial. However, in special circumstances, patients who carry germ-line mismatch repair cancer- causing mutations should be offered this option as an alternative to lifetime colonoscopic surveillance. Church and Lynch have suggested that prophylactic surgery should be an option for patients who are likely to show reduced compliance with colonoscopy. Genetic counseling, coupled with a second surgical opinion, must be provided so that patients can evaluate the various available surgical management strategies.
Prophylactic Hysterectomy and Oophorectomy
Women at risk for Lynch syndrome should have annual screening for endometrial and ovarian cancer beginning at age 30 to 35 years. Endometrial aspiration coupled with transvaginal ultrasound is advised for screening. CA-125 testing should be performed semiannually for ovarian cancer. Women must be advised of the marked limitations in ovarian cancer screening. Prophylactic hysterectomy and oophorectomy can be considered when childbearing is completed.
The cancer genetics diagnostician has often been thought of as someone who is obsessed with the minutiae of the cancer family history, which were believed by many colleagues to be of only minor public health significance. But no longer! The magnitude of hereditary cancer problems now compels physicians to be more strongly focused upon these concerns. Indeed, the public is demanding this attention, and malpractice attorneys are learning to deal with these multifaceted issues.[56,57]
On a more positive note, molecular geneticists have discovered countless deleterious germ-line mutations that have enabled the identification, diagnosis, and management of an increasing number of hereditary cancer syndromes. When used effectively in the clinical practice setting by informed physicians, these discoveries can significantly enhance medical management of hereditary cancer-prone families. For example, the presence of a cancer-causing mutation in a patient with a hereditary cancer syndrome enables the knowledgeable physician to offer that individual appropriate surveillance and management procedures. Conversely, in a family where a known cancer-causing mutation exists, the absence of that mutation in a family member means that general population cancer guidelines can be utilized for that individual. Such common hereditary cancers as those of the colon and endometrium in patients with Lynch syndrome (ie, MSH2, MLH1, and MSH6 mutations), and of the breast and ovary in patients with HBOC syndrome (ie, BRCA1/BRCA2 mutations) head the list of cancer disorders that are amenable to highly targeted surveillance protocols.
Research at the basic science level should one day lead to the identification of those presently elusive germline variants that confer an increased susceptibility (or resistance) to cancer. This will require a better elucidation of the myriad complex somatic genetic events that occur in the emerging cell. With increasing knowledge about cancer causality at the molecular level during the past decade, the clinical translation of cancer "running in families" has become a source of major contention.
Barriers to Cancer Control
Unfortunately, these cancer control opportunities may be seriously compromised given most physicians' limited knowledge or interest in what constitutes a hereditary cancer syndrome, and the significance of highly targeted cancer surveillance and specialized management protocols for particular disorders. Further confounders to cancer control center around the perception of many patients at risk for hereditary cancer that participating in genetic testing, genetic counseling, and pertinent clinical cancer control measures will identify them as being a member of a family with a hereditary cancer-prone syndrome. They may then reason that this information will result in discrimination by insurance companies or employers. To help ameliorate these concerns, we need legislation that will provide protection from such potential discrimination.
Finally, there remain countless areas in the etiology, pathogenesis, and control of HNPCC that require continued intensive research. Some of the questions to be answered are:
(1) What is the complete tumor complement of HNPCC? (2) What are the chemotherapy and chemoprevention implications of this disease? (3) Can we improve surveillance/ management strategies? (4) Can we achieve molecular-based chemoprevention? (5) What are the genotypic and phenotypic heterogeneity implications of Lynch syndrome? (6) What are the differential diagnostic implications of the disease?
Our research efforts and those of colleagues throughout the world have only grazed the tip of the proverbial iceberg in terms of the etiology, pathogenesis, surveillance, and management of Lynch syndrome. What we do know clearly is that the knowledge accrued to date, when translated clinically, can save lives!
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgement: This manuscript was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents 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. Support was also received from NIH Grant #1U01 CA86389, and through a grant awarded by the Jacqueline Seroussi Memorial Foundation.