The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families.

The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.

Long Term Outcomes of a Geriatric Liaison Intervention in Frail Elderly Cancer Patients.

BACKGROUND: The aim of this study was to evaluate the long term effects after discharge of a hospital-based geriatric liaison intervention to prevent postoperative delirium in frail elderly cancer patients treated with an elective surgical procedure for a solid tumour. In addition, the effect of a postoperative delirium on long term outcomes was examined. METHODS: A three month follow-up was performed in participants of the Liaison Intervention in Frail Elderly study, a multicentre, prospective, randomized, controlled trial. Patients were randomized to standard treatment or a geriatric liaison intervention. The intervention consisted of a preoperative geriatric consultation, an individual treatment plan targeted at risk factors for delirium and daily visits by a geriatric nurse during the hospital stay. The long term outcomes included: mortality, rehospitalisation, Activities of Daily Living (ADL) functioning, return to the independent pre-operative living situation, use of supportive care, cognitive functioning and health related quality of life. RESULTS: Data of 260 patients (intervention n = 127, Control n = 133) were analysed. There were no differences between the intervention group and usual-care group for any of the outcomes three months after discharge. The presence of postoperative delirium was associated with: an increased risk of decline in ADL functioning (OR: 2.65, 95% CI: 1.02-6.88), an increased use of supportive assistance (OR: 2.45, 95% CI: 1.02-5.87) and a decreased chance to return to the independent preoperative living situation (OR: 0.18, 95% CI: 0.07-0.49). CONCLUSIONS: A hospital-based geriatric liaison intervention for the prevention of postoperative delirium in frail elderly cancer patients undergoing elective surgery for a solid tumour did not improve outcomes 3 months after discharge from hospital. The negative effect of a postoperative delirium on late outcome was confirmed. TRIAL REGISTRATION: Nederlands Trial Register, Trial ID NTR 823.