Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.
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.
Lindor
Noralane M
NM
Department of Medical Genetics, Mayo Clinic, Rochester, Minn, USA. nlindor@mayo.edu
Rabe
Kari
K
Petersen
Gloria M
GM
Haile
Robert
R
Casey
Graham
G
Baron
John
J
Gallinger
Steve
S
Bapat
Bharati
B
Aronson
Melyssa
M
Hopper
John
J
Jass
Jeremy
J
LeMarchand
Loic
L
Grove
John
J
Potter
John
J
Newcomb
Polly
P
Terdiman
Jonathan P
JP
Conrad
Peggy
P
Moslein
Gabriella
G
Goldberg
Richard
R
Ziogas
Argyrios
A
Anton-Culver
Hoda
H
de Andrade
Mariza
M
Siegmund
Kim
K
Thibodeau
Stephen N
SN
Boardman
Lisa A
LA
Seminara
Daniela
D
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
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