___________________________________________________________________________ Colorectal Cancer
MSH2 , MLH1 , PMS1 , PMS2 , or MSH6 . In affected families, 15% to 60% of family members possess MSH2 or MLH1 mutations [91; 96; 97]. Lynch syndrome is an autosomal dominant disorder in which families and patients possess a germline mutation in a DNA MMR gene or loss of expression of the MSH2 gene due to dele- tion in the EPCAM gene. These genes function to maintain DNA fidelity during replication and are inactivated in Lynch syndrome [90; 98]. Genetic Testing . Genetic risk assessment of Lynch syndrome considers family cancer history and patient age if diagnosed with colorectal cancer or malignancies associated with Lynch syndrome. Mutation in MMR genes can be detected using immunohistochemistry techniques (IHCs) or DNA micro- satellite instability (MSI) analysis. Several validated computer models predict MMR gene mutation probability (even when MSI or IHC information is absent) and also incorporate fam- ily history of endometrial cancer. Mutation detection rates are higher for patients with more striking family histories or informative tumor testing data [99; 100]. Clinical Features . Colorectal cancer and extracolonic malig- nancies are the primary consequences of Lynch syndrome. Colorectal cancer associated with Lynch syndrome is character- ized by early age of onset, excess synchronous and metachro- nous colorectal neoplasm, right-sided dominance (roughly 67%), and extracolonic tumors. The average age of colorectal cancer diagnosis in patients with Lynch syndrome is 44 to 52 years, versus 71 years in sporadic colorectal cancer. MLH1 and MSH2 account for close to 90% of gene mutations, and the lifetime risk of colorectal cancer in MLH1 and MSH2 mutation carriers is 68.7% in men and 52% in women [98]. Risk of extracolonic malignancy is greatest for endometrial cancer. At least one female member in about half of all Lynch syndrome pedigrees is affected, and 50% of women with an MMR gene mutation present with endometrial cancer as first malignancy. Patients with Lynch syndrome have an elevated risk of several other cancers. Risk of extracolonic tumor devel- opment by 70 years of age in Lynch syndrome is shown below, with prevalence rate ranges reflecting differences between specific MMR mutations [98]: • Endometrial ( MLH1/MSH2 ): 14% to 54% • Ovarian: 4% to 20% • Urinary tract: 0.2% to 25% • Stomach: 0.2% to 13% • Small bowel: 0.4% to 12% • Brain/central nervous system: 1% to 4%
The adenoma-carcinoma sequence of polyp-to-cancer dwell time is an estimated mean 35 months, considerably more rapid than the 10- to 15-year average in sporadic colorectal cancer. This accelerated rate is likely the result of MMR gene dysfunc- tion that creates frequent DNA mismatches in multiple genes to disrupt their normal function [98]. Until recently, Lynch syndrome was termed hereditary nonpolyposis colorectal can- cer, a misnomer because polyps are usually present [88; 101]. Diagnosis . Clinical criteria to identify patients with Lynch syndrome were published in 1990 and termed the Amsterdam criteria. These were revised and expanded with the 1999 Amsterdam II criteria, which included extracolonic cancers. The Amsterdam II defines minimum criteria for a clinical diagnosis of Lynch syndrome as at least three relatives with a Lynch-associated cancer (e.g., colorectal cancer, endometrial, small bowel, ureter, renal pelvis) and [88; 96; 102]: • Two or more successive generations affected • One or more relatives diagnosed before 50 years of age (at least one first-degree relative) • FAP excluded • Tumors verified by pathologic examination The 2004 updated Bethesda Guidelines were developed to improve the false-negative rates with Amsterdam II and outline criteria to prompt MSI tumor testing to identify Lynch syn- drome. Tumors meeting one or more of these criteria require testing for MSI [88; 96; 98; 103]: • Colorectal cancer diagnosed at 50 years of age or younger • Synchronous or metachronous Lynch-associated cancer present, regardless of age • Colorectal cancer with Lynch-like histology (e.g., tumor infiltrating lymphocytes, Crohn-like
lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) in patients younger than 60 years of age
• Colorectal cancer in a patient with one or more first-degree relatives with Lynch-associated cancer diagnosed at or before 50 years of age • Colorectal cancer in a patient with two or more first- or second-degree relatives with a Lynch-associated tumor, regardless of age Although more sensitive than Amsterdam II in identifying families with Lynch syndrome, only 15% to 30% of families not meeting Amsterdam II but meeting Bethesda criteria exhibit MSI gene mutation. Thus, Amsterdam II or Bethesda criteria may be used to help identify patients who should receive genetic testing, but they should not be used as diag- nostic instruments [96; 104]. With the advent of alternative approaches, including universal testing of all newly diagnosed cases of colorectal cancer for MSI (regardless of age at diag- nosis or family history of cancer), clinical criteria for Lynch
• Prostate: 9% to 30% • Breast: 5% to 18%
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