Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands

Background: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. Methods: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). Results: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8–2.3) and 5.4 months (95% CI, 4.0–6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0–1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. Conclusions: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. Funding: Johannes J.M. Kwakman received an unrestricted research grant from Servier

Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Changes in body size and body composition in survivors of childhood cancer:seven years follow-up of a prospective cohort study

Background & aims: Cancer treatment is known to have impact on nutritional status, and both underweight and overweight have been reported in several studies in survivors. A limitation of most studies is that they relied on retrospective data or were limited to a subgroup of patients. The current study aims to describe changes in body size and body composition prospectively seven years after diagnosis in a heterogeneous sample of childhood cancer survivors and to evaluate associated factors. Methods: The study population consisted of children diagnosed with hematological, solid and brain malignancies aged 0–18 years at diagnosis. Data of body size, body composition, and associated factors were collected at diagnosis, one year and seven years after diagnosis. Results: In the total cohort mean BMI z-score increased during treatment. In children with hematological and brain malignancies BMI z-score continued to increase after end of treatment leading to quadrupling of the prevalence of obesity seven years after diagnosis. BMI at diagnosis (β = −0.34, P = 0.007) and maternal BMI (β = 0.25, P = 0.046) were associated with the increase in BMI z-score. Mean fat mass (FM) z-score, already high at diagnosis, increased during treatment in children with hematological and brain malignancies and evened out during follow-up. Changes in FM z-score were predicted by type of malignancy (hematologic malignancy versus solid tumor β = 0.48, P = 0.008; brain tumor versus solid tumor β = 0.45, P = 0.012). Mean fat free mass (FFM) z-scores started low at diagnosis, particularly in patients with brain tumors, increased during treatment in patients with solid and brain malignancies, though decreased in children with hematological malignancies. At 7 years follow-up a clear increase to normal was seen. Age at diagnosis (β = 0.43, P = 0.004) and initial FFM (β = −0.49, P = 0.001) were found to be significant predictors for changes in FFM z-scores. Conclusions: The finding that the once obtained extra weight and FM during treatment persisted after termination of treatment in children with hematological and brain malignancies, stresses the importance to create awareness about the risk of developing overweight in children during cancer treatment

PRODH rs450046 and proline x COMT Val(158)Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome

22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes. Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS. Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val(158)Met. Plasma proline levels, FSIQ, SR and PPI were measured. Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 μmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η (2) = 0.15). A significant interaction effect of proline levels and COMT Val(158)Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η (2) = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val(158)Met genotype effect on SR was stronger than in subjects with normal proline levels. Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorder