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

Departments of Medical Genetics (Dr Lindor), Health Sciences Research (Ms Rabe and Drs Petersen and de Andrade), and Laboratory Medicine (Dr Thibodeau), and Division of Gastroenterology (Dr Boardman), Mayo Clinic, Rochester, Minn; University of Southern California, Los Angeles (Drs Haile and Siegmund); Cleveland Clinic, Cleveland, Ohio (Dr Casey); Dartmouth Medical School, Hanover, NH (Dr Baron); Mount Sinai Hospital, University of Toronto, Toronto, Ontario (Drs Gallinger and Bapat and Ms Aronson); University of Melbourne, Melbourne, Australia (Dr Hopper); McGill University, Montreal, Quebec (Dr Jass); University of Hawaii Cancer Research Center, Honolulu (Drs LeMarchand and Grove); Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Wash (Drs Potter and Newcomb); Department of Cancer Biology, University of San Francisco, San Francisco, Calif (Dr Terdiman and Ms Conrad); Department of Surgery, Heinrich Heine University, Düsseldorf, Germany (Dr Moslein); University of North Carolina, Chapel Hill (Dr Goldberg); University of California, Irvine (Drs Ziogas and Anton-Culver); and Division of Cancer Control and Population Sciences, Clinical and Genetic Epidemiology Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md (Dr Seminara).

Corresponding Author: Noralane M. Lindor, MD, Mayo Foundation, 200 First St SW, Rochester, MN 55905 ([email protected]).

Author Contributions: Dr Lindor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lindor, Rabe, Petersen, Goldberg, de Andrade, Boardman.

Acquisition of data: Lindor, Rabe, Petersen, Baron, Gallinger, Aronson, Hopper, Jass, LeMarchand, Grove, Potter, Newcomb, Terdiman, Conrad, Moslein, Goldberg, Anton-Culver, Thibodeau, Boardman.

Analysis and interpretation of data: Lindor, Rabe, Petersen, Haile, Casey, Baron, Bapat, Hopper, LeMarchand, Potter, Newcomb, Goldberg, Ziogas, de Andrade, Siegmund, Seminara.

Drafting of the manuscript: Lindor, Rabe, Petersen, Baron, Hopper, Moslein, Anton-Culver.

Critical revision of the manuscript for important intellectual content: Lindor, Rabe, Petersen, Haile, Casey, Baron, Gallinger, Bapat, Aronson, Hopper, Jass, LeMarchand, Grove, Potter, Newcomb, Terdiman, Conrad, Moslein, Goldberg, Ziogas, de Andrade, Siegmund, Thibodeau, Boardman, Seminara.

Statistical analysis: Lindor, Rabe, Haile, Ziogas, de Andrade, Siegmund.

Obtained funding: Lindor, Petersen, Gallinger, Hopper, Jass, LeMarchand, Grove, Potter, Newcomb, Seminara.

Administrative, technical, or material support: Lindor, Petersen, Casey, Hopper, Jass, Goldberg, Anton-Culver, Thibodeau, Boardman.

Study supervision: Lindor, Petersen, Hopper, Moslein.

Financial Disclosures: None reported.

Funding/Support: This work was supported by the National Cancer Institute, National Institutes of Health, under RFA CA-95-011 and through cooperative agreements with the members of the Colon Cancer Family Registry and principal investigators.

Role of the Sponsors: The National Cancer Institute and the Colon Cancer Family Registry had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Disclaimer: The content of this article does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cooperative Family Registries, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the Cooperative Family Registry. Collaborating centers include the Australian Colorectal Cancer Family Registry (UO1 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (UO1 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (UO1 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (UO1 CA074783), Seattle Colorectal Cancer Family Registry (UO1 CA074794), University of Hawaii Colorectal Cancer Family Registry (UO1 CA074806), and University of California, Irvine Informatics Center (UO1 CA078296).

Acknowledgment: We thank the many families who have participated in research studies that facilitated this specific study. We also thank the following individuals for their assistance in this study: Kristin Lee, John Hake, Hema Vankayala, MD, Robert Vierkant, MAS, and Duncan Thomas, PhD.

JAMA: The Journal of the American Medical Association 293(16):p 1979-1985, April 27, 2005.

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.