Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency: Familial Colorectal Cancer Type X

University of Toronto, Toronto, Ontario, Canada
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 05/2005; 293(16):1979-85. DOI: 10.1001/jama.293.16.1979
Source: PubMed


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.
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.
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.
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.
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).
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.

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    • "The following tumour characteristics were abstracted from the clinical histopathology report and/or from pathologist review: location, size, nodal status, differentiation, histologic type, and presence/absence of peritumoural lymphocytes, Crohn's-like reaction, tumour-infiltrating lymphocytes, and venous invasion. MSI and/or IHC were performed on all tumour samples (Lindor et al, 2005; Newcomb et al, 2007). Cases were allocated to one of the three groups: (1) 'LS' (n ¼ 312) for cases meeting AC1 and whose tumours were classified as MSI (MSI-high and/or MMR-deficient), (2) 'FCCTX' (n ¼ 177) for cases meeting AC1, but with non-MSI tumours, or (3) 'non-AC1' (n ¼ 12,175) for the remainder of CRC cases whose family histories did not meet AC1. "
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    ABSTRACT: Background: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases. Methods: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. Results: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. Conclusions: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.
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    • "The Bethesda Guidelines formulated in 1996 and revised in 2004 [48,49] incorporate broader age and family history criteria, but also include the unique histopathological features associated with Lynch tumors (tumor-infiltrating lymphocytes, signet ring cells, mucinous and poorly differentiated histology) as a fifth criteria (Table 2 ). The novelty of the Bethesda Guidelines was the introducing of MSI testing in colorectal tumors that fulfill the criteria as a mandatory step in the diagnosis of Lynch Syndrome. "
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    • "The definition of what comprises LS has been refined in recent years with the initiation of molecular genetic testing and tumor analyses (Weissman et al. 2011). Lynch syndrome (LS) is now the commonly accepted designation (Boland 2005; Jass 2006; Lindor et al. 2005) and refers to instances where there is molecular evidence of a germline MMR defect. Familial colon cancer and/or families that meet Amsterdam I criteria (ACI) in the absence of a MMR defect are sometimes referred to as " Familial Colorectal Cancer Type X " (Jass 2006; Lindor et al. 2005; Lindor 2009). "
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