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

Abstract

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.

Figure 1

Cumulative Age of Onset of Colorectal Cancer in Primary- and Secondary-Zone Relatives in Families Fulfilling Amsterdam-I Criteria and Distribution of Colorectal Cancer Diagnoses in the SEER Registry Curves exclude the 3 affected family members used to define the Amsterdam-I criteria. MSI-H indicates microsatellite instability–high; MSI-L, microsatellite instability–low; MSS, microsatellite stable; SEER, Surveillance, Epidemiology, and End Results.

Figure 2

Categories of Colorectal Cancer Syndromes Schematic showing the 2 categories of colorectal cancer syndromes, illustrating that nonpolyposis disorders are heterogeneous but based on tumor biology can be distinguished as those having defective mismatch repair (Lynch syndrome; group A) and those with proficient mismatch repair (group B in this study, called here familial colorectal cancer type X). Diagram excludes syndromes characterized by hamartomatous/hyperplastic polyposis. *Defined by any number of pedigree and/or laboratory criteria, including but not limited to the Amsterdam criteria. Hereditary nonpolyposis colon cancer syndrome is the term that has traditionally been used in this context, encompassing those entities that have emerged as distinguishable clinical entities (ie, Lynch syndrome and familial colorectal cancer type X).