Advances in the assessment of minimal residual disease in mantle cell lymphoma.

The clinical impact of minimal residual disease detection at early time points or during follow-ups has been shown to accurately predict relapses among patients with lymphomas, mainly in follicular and diffuse large B cell lymphoma. The field of minimal residual disease testing in mantle cell lymphoma is still evolving but has great impact in determining the prognosis. Flow cytometry and polymerase chain reaction-based testing are most commonly used methods in practice; however, these methods are not sensitive enough to detect the dynamic changes that underline lymphoma progression. Newer methods using next-generation sequencing, such as ClonoSeq, are being incorporated in clinical trials. Other techniques under evolution include CAPP-seq and anchored multiplex polymerase chain reaction-based methods. This review article aims to provide a comprehensive update on the status of minimal residual disease detection and its prognostic effect in mantle cell patients. The role of circulating tumor DNA-based minimal residual disease detection in lymphomas is also discussed.

Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma.

BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.

Assessment of glioma risk associated with an inherited variant at chromosome 11q23.

It is still unclear whether or not rs498872 at 11q23.3 increases the risk of developing glioma, because the previous literature has reported mixed findings. We carried out a meta-analysis with an aim to test the hypothesis that rs498872 contributes to the development of glioma. Eligible studies were identified through databases including the Chinese biomedical literature database, China national knowledge infrastructure, Science Direct, Embase and PubMed. The risk of glioma (OR and 95% CI) was evaluated with the fixed-effects model or the random-effects model. Sensitivity analysis and publication bias tests were performed to check the reliability of our findings. Ten independent populations representing three ethnicities were analyzed in this study. We found 1.17-1.34-fold increased risk of glioma associated with rs498872 genotypes (OR 1.34, 95% CI 1.22-1.46; OR 1.24, 95% CI 1.14-1.35; OR 1.20, 95% CI 1.10-1.31; OR 1.17, 95% CI 1.08-1.27). In the stratified analysis by ethnicity, we also observed a significant increase in the risk of glioma in both Americans and Europeans. The results of our study support that the rs498872 polymorphism at 11q23.3 locus may be an important risk factor for glioma risk.

Copy number alterations at polymorphic loci may be acquired somatically in patients with myelodysplastic syndromes.

Loss of genomic integrity is thought to be one of the underlying causes of myelodysplastic syndromes (MDS). However, it is unclear whether changes in copy number at loci that are common sites of copy number polymorphisms play a pathogenic role. Here we show that copy number changes in the MDS clone that occur at polymorphic loci are frequently somatic alterations rather than constitutional variants, and the extent of copy number changes at polymorphic loci is increased in CD34(+) cells of MDS patients compared to age-matched controls. This study suggests a potential pathophysiological role for copy number alterations at polymorphic loci in patients with MDS, and highlights the need for somatic control tissues for each patient studied in high-resolution genome-wide investigations.

Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management.

Primitive neuroectodermal tumors are in the Ewing's sarcoma family of tumors and are composed of small round cells. Because of their rare occurrence, optimal therapy is challenging, particularly if they occur in the head and neck. Diagnosis is based on history, immunostaining with at least 2 neural markers, ultrastructural examination, and evidence of an abnormal t(11;22)(q24;q12) translocation as the hallmark for the Ewing's sarcoma family. The prognosis in general is poor because of overt metastasis at the time of diagnosis. Of 27 reported patients with primitive neuroectodermal tumors of the head and neck, 23 were less than 20 years of age. Most patients presented with a tumor in the nasal cavity, paranasal sinuses, or neck. Symptoms developed rapidly (3.6 months, on average), and a lethal outcome occurred in 9 patients. This highly malignant tumor requires an aggressive combination of radical resection, chemotherapy, and radiotherapy. A close follow-up with regular radiographic examination for at least 5 years is mandatory.

Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients.

A hemizygous deletion of the q11 band on chromosome 22 occurs in 1 of every 5,950 live births (0.017%). The deletion is mediated by low copy repeats (LCRs) flanking this locus. Presence of the deletion is associated with variable phenotypic expression, which can include distinctive facial dysmorphologies, congenital heart disease and learning disabilities. An unusually high percentage of individuals with this deletion (25-30%) have been described to develop schizophrenia or schizoaffective disorder. In previous studies, the prevalence of the 22q11 deletion in patients with schizophrenia was found to be approximately 2% in Caucasian adults and 6% in childhood-onset cases. Both these frequencies represent a dramatic increase from the prevalence of the deletion in the general population. In this study, we investigate the occurrence of the 22q11 deletion in an independent sample of schizophrenic patients of Afrikaner origin. We first ascertained a sample of 85 patients who meet full diagnostic criteria for schizophrenia for presence of two or more of the clinical features associated with presence of the 22q11 deletion. A group of six patients (7%) met these criteria. This group was subjected to fluorescent in situ hybridization (FISH) and presence of the 22q11 deletion was confirmed for two subjects. Our study therefore confirms the previously reported rate of 2% frequency of the 22q11 deletion in adult schizophrenic patients and provides a two-stage screening protocol to identify these patients.

Chromosome-wide assessment of replication timing for human chromosomes 11q and 21q: disease-related genes in timing-switch regions.

The completion of the human genome sequence will greatly accelerate development of a new branch of bioscience and provide fundamental knowledge to biomedical research. We used the sequence information to measure replication timing of the entire lengths of human chromosomes 11q and 21q. Megabase-sized zones that replicate early or late in S phase (thus early/late transition) were defined at the sequence level. Early zones were more GC-rich and gene-rich than were late zones, and early/late transitions occurred primarily at positions identical to or near GC% transitions. We also found the single nucleotide polymorphism (SNP) frequency was high in the late-replicating and replication-transition regions. In the early/late transition regions, concentrated occurrence of cancer-related genes that include CCND1 encoding cyclin D1 (BCL1), FGF4 (KFGF), TIAM1 and FLI1, was observed. The transition regions contained other disease-related genes including APP associated with familial Alzheimer's disease (AD1), SOD1 associated with familial amyotrophic lateral sclerosis (ALS1) and PTS associated with phenylketonuria. These findings are discussed with respect to the prediction that increased DNA damage occurs in replication-transition regions. We propose that genome-wide assessment of replication timing serves as an efficient strategy for identifying disease-related genes.

Molecular analysis of the beta-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the beta(S) Senegal mutation.

A large and ethnically well-defined Mandenka sample from eastern Senegal was analyzed for the polymorphism of the beta-globin gene cluster on chromosome 11. Five RFLP sites of the 5' region were investigated in 193 individuals revealing the presence of 10 different haplotypes. The frequency of the sickle-cell anemia causing mutation (beta(S)) in the Mandenka estimated from this sample is 11.7%. This mutation was found strictly associated with the single Senegal haplotype. Approximately 600 bp of the upstream region of the beta-globin gene were sequenced for a subset of 94 chromosomes, showing the presence of four transversions, five transitions, and a composite microsatellite polymorphism. The sequence of 22 beta(S) chromosomes was also identical to the previously defined Senegal haplotype, suggesting that this mutation is very recent. Monte Carlo simulations (allowing for a specific balancing selection model, a logistic growth of the population, and variable initial frequencies of the Senegal haplotype) were used to estimate the age of the beta(S) mutation. Resulting maximum-likelihood estimates are 45-70 generations (1,350-2,100 years) for very different demographic scenarios. Smallest confidence intervals (25-690 generations) are obtained under the hypothesis that the Mandenka population is large (N(e) >5,000) and stationary or that it has undergone a rapid demographic expansion to a current size of >5,000 reproducing individuals, which is quite likely in view of the great diversity found on beta(A) chromosomes.

Polymerase chain reaction-based risk assessment for Wilms tumor in sporadic aniridia.

PURPOSE: Sporadic cases of aniridia have a 30% risk for the development of Wilms tumor. Current guidelines for sporadic aniridia recommend screening by renal ultrasonography for the presence of tumors every 6 months until age 5 years. Deletions of chromosome 11p13 that affect both PAX6 (aniridia) and WT1 (Wilms tumor) loci are the basis for the association of these two uncommon disorders. We sought to develop a rapid polymerase chain reaction-based test that could rule out a chromosome 11p13 deletion covering the PAX6-WT1 region in sporadic aniridia. METHODS: Five patients with sporadic aniridia were recruited. Polymerase chain reaction-based genotyping was carried out for six highly informative marker loci across the PAX6-WT1 region to determine whether these patients had one or two haplotypes. The results were compared with those obtained from two cell lines with known deletions in the PAX6-WT1 region. RESULTS: All five patients were heterozygous at least at one of the four marker loci in the PAX6-WT1 region, indicating that there were no cases of gross chromosomal deletion. The cell lines showed hemizygosity in the four marker loci within the PAX6-WT1 region and in one of the two flanking marker loci. CONCLUSIONS: We have developed a rapid DNA test with an estimated sensitivity of 94.0% to 99.2%, using standard DNA diagnostic techniques and equipment, to rule out chromosomal deletion in sporadic aniridia. Patients in whom a chromosome 11p13 deletion has been ruled out do not require repeated renal imaging to screen for Wilms tumor.