Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X

Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA : the journal of the American Medical Association 293:1979-1985

CONTEXT: Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown. OBJECTIVE: To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities. DESIGN, SETTING, AND PARTICIPANTS: Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses. MAIN OUTCOME MEASURES: Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. RESULTS: Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001). conclusions:="" families="" who="" fulfill="" ac-i="" criteria="" but="" who="" have="" no="" evidence="" of="" a="" dna="" mmr="" defect="" do="" not="" share="" the="" same="" cancer="" incidence="" as="" families="" with="" hnpcc-lynch="" syndrome="" (ie,="" hereditary="" mmr="" deficiency).="" relatives="" in="" such="" families="" have="" a="" lower="" incidence="" of="" colorectal="" cancer="" than="" those="" in="" families="" with="" hnpcc-lynch="" syndrome,="" and="" incidence="" may="" not="" be="" increased="" for="" other="" cancers.="" these="" families="" should="" not="" be="" described="" or="" counseled="" as="" having="" hnpcc-lynch="" syndrome.="" to="" facilitate="" distinguishing="" these="" entities,="" the="" designation="" of="" "familial="" colorectal="" cancer="" type="" x"="" is="" suggested="" to="" describe="" this="" type="" of="" familial="" aggregation="" of="" colorectal="">