ABSTRACT
BACKGROUND: We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy. METHODS: One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy. RESULTS: The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59-6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79-3.93) and 2.05 (1.41-2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed. CONCLUSIONS: The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Checkpoint Kinase 2/genetics , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Chemotherapy, Adjuvant/methods , Disease-Free Survival , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Mutation/geneticsABSTRACT
Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.
