title: Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Genetics, Mayo Clinic, Rochester, Minn, USA. nlindor@mayo.edu
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Kari
authors.initials: K
authors.lastname: Rabe
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: John
authors.initials: J
authors.lastname: Baron
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: Melyssa
authors.initials: M
authors.lastname: Aronson
authors.forename: John
authors.initials: J
authors.lastname: Hopper
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jass
authors.forename: Loic
authors.initials: L
authors.lastname: LeMarchand
authors.forename: John
authors.initials: J
authors.lastname: Grove
authors.forename: John
authors.initials: J
authors.lastname: Potter
authors.forename: Polly
authors.initials: P
authors.lastname: Newcomb
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Terdiman
authors.forename: Peggy
authors.initials: P
authors.lastname: Conrad
authors.forename: Gabriella
authors.initials: G
authors.lastname: Moslein
authors.forename: Richard
authors.initials: R
authors.lastname: Goldberg
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Kim
authors.initials: K
authors.lastname: Siegmund
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008403:Mass Screening; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000145:classification / Q000453:epidemiology / Q000235:genetics; D009687:Nuclear Proteins; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018570:Risk Assessment; D018426:SEER Program
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein