• Noralane M Lindor, Kari Rabe, Gloria M Petersen, Robert Haile, Graham Casey, John Baron, Steve Gallinger, Bharati Bapat, Melyssa Aronson, John Hopper, Jeremy Jass, Loic LeMarchand, John Grove, John Potter, Polly Newcomb, Jonathan P Terdiman, Peggy Conrad, Gabriella Moslein, Richard Goldberg, Argyrios Ziogas, Hoda Anton-Culver, Mariza de Andrade, Kim Siegmund, Stephen N Thibodeau, Lisa A Boardman, and Daniela Seminara.
• Department of Medical Genetics, Mayo Clinic, Rochester, Minn, USA. nlindor@mayo.edu
• JAMA. 2005 Apr 27; 293 (16): 197919851979-85.

ContextApproximately 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.ObjectiveTo 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 ParticipantsIdentification (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 MeasuresCancer 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.ResultsGroup 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).ConclusionsFamilies 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 cancer.

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