Clinical prospects and research progress in hereditary non-polyposis colorectal cancer
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Abstract:
Hereditary non-polyposis colorectal cancer (HNPCC),also called Lynch syndrome,is an autosomal-dominantly inherited disease and is associated with germline mutations in mismatch repair(MMR)genes and microsatellite instability(MSI).HNPCC is the most common form of hereditary colorectal cancer,accounting for 5%-15% of colorectal cancers.HNPCC has characteristic clinicpathological features,such as right-sided predominance,more synchronous or metachronous multiple primary colorectal cancer, young age at diagnosis,and poor histopathological differentiation.Recently,surgery has been the main means of treating HNPCC.However,COX-2 inhibitors may be a new therapeutic approach. Recent molecular biology studies have deepened our understanding of its the biological behavior and therapy.Keywords:
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6564 Background: HNPCC, the most common cause of hereditary colorectal cancer (CRC), is inherited in an autosomal dominant fashion and caused by micro satellite instability and mutations in mismatch repair genes. Affected patients (pts) and first degree relatives tend to develop colonic and extra colonic tumors that need to be tested for the mutations. Genetic consultation (GC) should be routinely offered to the affected pts and relatives. To assess the utilization of GC, we assessed the frequency of referral for GC for the presence of HNPCC syndrome at our medical center. Methods: Patients with CRC were identified from the tumor registry at the University of Arkansas for Medical Sciences (UAMS) and the Central Arkansas Veterans Healthcare System (CAVHS) from January 1 st 2000 to September, 2006. Pts’ charts were reviewed for synchronous or metachronous HNPCC tumors and family history (FH). FH was categorized as positive according to the Bethesda criteria (BC, 2000–2002), revised Bethesda criteria (RBC, 2003–2006), negative (documented FH but no h/o cancer) or inadequate documentation. Percentage of pts with positive FH for HNPCC syndrome and those with CRC less than 50 years of age (for pts diagnosed 2003–2006) who were referred for GC was calculated. The list of these pts was cross referenced to the list in genetics clinic at UAMS and CAVHS. Results: 858 patient charts were reviewed. Table 1 shows the number of pts meeting criteria for genetic counseling. 138 (16%) pts had inadequate /no documented FH. Of the 720 pts with documented FH, 67 (9.3%) had positive FH and 126(17%) met BC / RBC. Only 13 (10.3%) of 126 pts were referred for genetic counseling. The number of pts eligible for GC increased with inclusion of RBC. However, the percentage of eligible pts referred for GC was extremely low. Conclusions: FH is not adequately documented in many pts presenting with CRC. Only a small percentage of pts who qualify for GC are referred. Education of health care providers for referral to genetics counseling is warranted. No significant financial relationships to disclose. [Table: see text]
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Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer. It is characterized by early onset of colorectal cancer and other extracolonic-associated malignancies. This disorder is inherited in an autosomal dominant pattern and is due to a mutation in one of the DNA mismatch repair genes. Although clinical and molecular understanding of the syndrome has progressed dramatically in the last decade, diagnosis of the syndrome is still a clinical challenge. This review summarizes the main features of the syndrome and provides an update of its management.
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Introduction Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment.Areas covered The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed.Expert commentary LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.
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Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 3% to 5% of all colorectal cancer. HNPCC is caused by germline mutations in the mismatch repair system and is recognized by a characteristic clinical phenotype as well as a hallmark of the tumors termed “microsatellite instability.” Microsatellite instability serves as a molecular fingerprint for defective mismatch repair and has proven to be useful in the molecular diagnostic workup for HNPCC. The crystal structure of the DNA mismatch repair protein MutS has been solved, providing insight into the molecular basis of defective mismatch repair. Genetic testing has become a key component of the treatment of patients and families with HNPCC, and enhanced surveillance for HNPCC has been shown to reduce the rate of colorectal cancer by more than half and improve 10-year survival from 68% to 93%.
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Colorectal cancer (CRC) is one of the most common cancer worldwide with approximately 2 to 5% of all colon cancers are associated with well-defined hereditary factors. Hereditary nonpolyposis colorectal cancer (Hereditary Nonpolyposis Colorectal Cancer), also known as Lynch syndrome (LS), is the most common form of hereditary CRC characterized by an early age of onset and follows the autosomal dominant inheritance pattern. HNPCC is caused by the alteration in four mismatch repair (MMR) genes. Immunohistochemistry (IHC) and microsatellite instability (MSI) testing, followed by conventional Sanger sequencing reliably identify the majority of mutations. However, methods to identify other underlying variants or genomic rearrangements of HNPCC have emerged. In addition to the clinical characterization and evaluation of HNPCC patients, the implementation of screening strategies for both affected and unaffected CRC patients together with the accelerated advancement in molecular testing methods will shed light on a more comprehensive detection of HNPCC. In this review, the approaches for the selection of high-risk HNPCC and molecular testing performed over the past few years are discussed.
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