Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations.
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
A B S T R A C T PurposeFluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
Patients and MethodsWe tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n ϭ 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.
ResultsGlobal capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846TϾA and *2A (combined odds ratio, 5.51; P ϭ .0013) and with the common TYMS polymorphisms 5ЈVNTR2R/3R and 3ЈUTR 6bp ins-del (combined odds ratio, 1.31; P ϭ 9.4 ϫ 10 Ϫ6 ). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.
ConclusionA panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
Background and aims: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development-namely, that a desmoplastic reaction can favour either the host or the tumour-it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. Methods: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. Results: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p,0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. Conclusion: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.
We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totalling 21,096 cases and 19,555 controls. We identified three novel CRC risk loci at 6p21 (rs1321311, near CDKN1A; P=1.14×10−10), 11q13.4 (rs3824999, intronic to POLD3; P=3.65×10−10) and Xp22.2 (rs5934683, near SHROOM2; P=7.30×10−10) This brings to 20 the number of independent loci associated with CRC risk, and provides further insight into the genetic architecture of inherited susceptibility to CRC.
"Differentiation between septic arthritis and transient synovitis of the hip in children with clinical prediction algorithms." The Journal of Bone and Joint Surgery.86,5. 956-962. (2004 Background: Differentiation between septic arthritis and transient synovitis of the hip in children can be difficult.
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