Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency
Familial Colorectal Cancer Type X
- Lindor, Noralane M. MD
- Rabe, Kari MS
- Petersen, Gloria M. PhD
- Haile, Robert PhD
- Casey, Graham PhD
- Baron, John MD
- Gallinger, Steve MD
- Bapat, Bharati PhD
- Aronson, Melyssa MSc, CGC
- Hopper, John PhD
- Jass, Jeremy MD
- LeMarchand, Loic MD, PhD
- Grove, John PhD
- Potter, John MD, PhD
- Newcomb, Polly PhD
- Terdiman, Jonathan P. MD
- Conrad, Peggy MS
- Moslein, Gabriella MD
- Goldberg, Richard MD
- Ziogas, Argyrios PhD
- Anton-Culver, Hoda PhD
- de Andrade, Mariza PhD
- Siegmund, Kim PhD
- Thibodeau, Stephen N. PhD
- Boardman, Lisa A. MD
- Seminara, Daniela PhD, MPH
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 cancer.