Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high‐penetrance genes

Abstract

We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16-year period (1990-2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8,612 families were identified. One hundred and sixteen of 1,631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high-penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.

Development and validation of a simple questionnaire for the identification of hereditary breast cancer in primary care

“…All pedigrees were reviewed by at least two clinical geneticists to assess presence of criteria for Li-Frameni syndrome, Li-Fraumeni-Like syndrome, HBCC or other cancer predisposition syndromes. For Li-Fraumeni syndrome, the original criteria described by Li and Fraumeni [12] were used; for Li-Fraumeni-Like syndrome, pedigrees were classified according to the criteria of Birch [13] and Eeles [14] and for HBCC, the Meijers-Heijboer and Nasseem criteria were used [15-38]. …”

CHEK2*1100delC Genotyping for Clinical Assessment of Breast Cancer Risk: Meta-Analyses of 26,000 Patient Cases and 27,000 Controls

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A B S T R A C T

Purpose CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice.

Patients and Methods

We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EM-BASE, and Web of Science. Among the 42 initially identified studies, we excluded double publications, [25][26][27][28][29][30]32,33,41 studies of ethnic groups other than those of Northern or Eastern European descent, [22][23][24]34,38,40,42,43,45,47 studies of breast cancer that occurred as part of a multicancer syndrome, 31,35,36 and studies of men with breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes.

Conclusion

These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer-predisposing gene, which increases the risk three-to five-fold.

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BRCA1, BRCA2 and CHEK2 c.1100 delC mutations in patients with double primaries of the breasts and/or ovaries

“…It is not clear why this analysis did not detect any difference between unilateral and bilateral cases although the selection criteria for testing meant that nearly all unilateral cases had a family history of breast cancer. The 2% frequency for CHEK2  c.1100delC is at least four times our local population rate 22. The largest series by Fletcher et al 20098 was ascertained from multiple sources including a UK series selected on family history.…”