RNF43 is frequently mutated in colorectal and endometrial cancers

We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.National Human Genome Research Institute (U.S.) (Grant U54HG003067

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds

Inherited DNA-Repair Defects in Colorectal Cancer

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi)

Systematic Identification of Rhythmic Genes Reveals <em>camk1gb</em> as a New Element in the Circadian Clockwork

<div><p>A wide variety of biochemical, physiological, and molecular processes are known to have daily rhythms driven by an endogenous circadian clock. While extensive research has greatly improved our understanding of the molecular mechanisms that constitute the circadian clock, the links between this clock and dependent processes have remained elusive. To address this gap in our knowledge, we have used RNA sequencing (RNA–seq) and DNA microarrays to systematically identify clock-controlled genes in the zebrafish pineal gland. In addition to a comprehensive view of the expression pattern of known clock components within this master clock tissue, this approach has revealed novel potential elements of the circadian timing system. We have implicated one rhythmically expressed gene, <em>camk1gb</em>, in connecting the clock with downstream physiology of the pineal gland. Remarkably, knockdown of <em>camk1gb</em> disrupts locomotor activity in the whole larva, even though it is predominantly expressed within the pineal gland. Therefore, it appears that <em>camk1gb</em> plays a role in linking the pineal master clock with the periphery.</p> </div

Effect of <i>camk1gb</i> knockdown on pineal <i>aanat2</i> and <i>otx5</i> mRNA rhythms.

<p>Zebrafish embryos injected with either control morpholino (black line) or <i>camk1gb</i> morpholino (gray line) were subjected to DD during their third day of development and pineal <i>aanat2</i> and <i>otx5</i> mRNA levels were determined by whole mount ISH. A) Embryos were sampled at 4-hr intervals for <i>aanat2</i>. Statistical differences in <i>aanat2</i> mRNA levels between the control morpholino and <i>camk1gb</i> morpholino injected embryos were determined by two-tailed <i>t</i>-test with Bonferroni correction (* P-value<0.05, ** P-value<0.01, *** P-value<0.001). B) Whole-mount ISH for <i>aanat2</i> in the heads (dorsal views) of representative larvae from each group, at CT14 and CT18. Arrows indicate pineal <i>aanat2</i> mRNA expression. C) <i>otx5</i> expression at CT18. Error bars represent SE (n = 10–15). CT = circadian time.</p

Genes detected as circadian using both DNA microarray and RNA–seq.

<p>Genes detected as circadian using both DNA microarray and RNA–seq.</p

<i>camk1gb</i> spatio-temporal expression.

<p>A) Rhythmic expression of <i>camk1gb</i> exclusively in the pineal glands (indicated by black arrows) of 48–72 hpf embryos as detected by whole mount ISH under constant darkness. B) Rhythmic expression of <i>camk1gb</i> in the zebrafish embryo (right) is correlated with the RNA-seq (solid line, left vertical axis) and the microarray data (dashed line, right vertical axis) from the adult (left). Correlation coefficients between the whole mount ISH results and the data obtained by microarrays and RNA-seq were determined by Pearson correlation (r = 0.89 and 0.77, respectively). For whole mount ISH, statistical differences in mRNA levels were determined by one-way ANOVA followed by a Tukey test (P-value<0.05). Error bars represent SE (n = 10–15). CT = circadian time. Gray and black bars represent subjective day and subjective night, respectively.</p