High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry

The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved. We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers. Prostate cancers (mean age at diagnosis = 62 ± SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H). Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50–83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01). MMR-deficient tumors had increased levels of tumor infiltrating lymphocytes compared with tumors without MMR-deficiency (p = 0.04). Under the assumption that tumour MMR-deficiency occurred only because the cancer was caused by the germline mutation, mutation carriers are at 3.2-fold (95 % CI 2.0–6.3) increased risk of prostate cancer, and when assessed by gene, the relative risk was greatest for MSH2 carriers (5.8, 95 % CI 2.6–20.9). Prostate cancer was the first or only diagnosed tumor in 37 % of carriers. MMR gene mutation carriers have at least a twofold or greater increased risk of developing MMR-deficient prostate cancer where the risk is highest for MSH2 mutation carriers. MMR IHC screening of prostate cancers will aid in identifying MMR gene mutation carriers

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Geometric and dosimetric evaluation of atlas based auto-segmentation of cardiac structures in breast cancer patients

Auto-segmentation represents an efficient tool to segment organs on CT imaging. Primarily used in clinical setting, auto-segmentation plays an increasing role in research, particularly when analyzing thousands of images in the "big data" era. In this study we evaluate the accuracy of cardiac dosimetric endpoints derived from atlas based auto-segmentation compared to gold standard manual segmentation. Heart and cardiac substructures were manually delineated on 54 breast cancer patients. Twenty-seven patients were used to build the auto-segmentation atlas, the other 27 to validate performance. We evaluated accuracy of the auto-segmented contours with standard geometric indices and assessed dosimetric endpoints. Auto-segmented contours overlapped geometrically with manual contours of the heart and chambers with Dice-similarity coefficients of 0.93 ± 0.02 (mean ± standard deviation) and 0.79 ± 0.07 respectively. Similarly, there was a strong link between dosimetric parameters derived from auto-segmented and manual contours (R  = 0.955-1.000). On the other hand, the left anterior descending artery had little geometric overlap (Dice-similarity coefficient 0.09 ± 0.07), though acceptable representation of dosimetric parameters (R  = 0.646-0.992). The atlas based auto-segmentation approach delineates heart structures with sufficient accuracy for research purposes. Our results indicate that quality of auto-segmented contours cannot be determined by geometric values only

DataSheet_1_Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome.pdf

Background and AimsTumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC.MethodsWe assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results.ResultsThe PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic.ConclusionsAmong patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification.</p

Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia

Specific genes, such as BCAT1 and IKZF1, are methylated with high frequency in colorectal cancer (CRC) tissue compared to normal colon tissue specimens. Such DNA may leak into blood and be present as cell-free circulating DNA. We have evaluated the accuracy of a novel blood test for these two markers across the spectrum of benign and neoplastic conditions encountered in the colon and rectum. Circulating DNA was extracted from plasma obtained from volunteers scheduled for colonoscopy for any reason, or for colonic surgery, at Australian and Dutch hospitals. The extracted DNA was bisulphite converted and analysed by methylation specific real-time quantitative PCR (qPCR). A specimen was deemed positive if one or more qPCR replicates were positive for either methylated BCAT1 or IKZF1 DNA. Sensitivity and specificity for CRC were estimated as the primary outcome measures. Plasma samples were collected from 2105 enrolled volunteers (mean age 62 years, 54 % male), including 26 additional samples taken after surgical removal of cancers. The two-marker blood test was run successfully on 2127 samples. The test identified 85 of 129 CRC cases (sensitivity of 66 %, 95 % CI: 57-74). For CRC stages I-IV, respective positivity rates were 38 % (95 % CI: 21-58), 69 % (95 % CI: 53-82), 73 % (95 % CI: 56-85) and 94 % (95 % CI: 70-100). A positive trend was observed between positivity rate and degree of invasiveness. The colonic location of cancer did not influence assay positivity rates. Gender, age, smoking and family history were not significant predictors of marker positivity. Twelve methylation-positive cancer cases with paired pre- and post-surgery plasma showed reduction in methylation signal after surgery, with complete disappearance of signal in 10 subjects. Sensitivity for advanced adenoma (n = 338) was 6 % (95 % CI: 4-9). Specificity was 94 % (95 % CI: 92-95) in all 838 non-neoplastic pathology cases and 95 % (95 % CI: 92-97) in those with no colonic pathology detected (n = 450). The sensitivity for cancer of this two-marker blood test justifies prospective evaluation in a true screening population relative to a proven screening test. Given the high rate of marker disappearance after cancer resection, this blood test might also be useful to monitor tumour recurrence. ACTRN1261100031898

In-Hospital Formula Use Increases Early Breastfeeding Cessation Among First-Time Mothers Intending to Exclusively Breastfeed

OBJECTIVE: To evaluate in-hospital formula supplementation among first time mothers who intended to exclusively breastfeed and determined if in-hospital formula supplementation shortens breastfeeding duration after adjusting for breastfeeding intention. STUDY DESIGN: We assessed strength of breastfeeding intentions prenatally in a diverse cohort of expectant primiparae and followed infant feeding practices through day 60. Among mothers planning to exclusively breastfed their healthy term infants for ≥1 week, we determined predictors, reasons, and characteristics of in-hospital formula supplementation; and calculated the intention-adjusted relative risk (ARR) of not fully breastfeeding days 30–60 and breastfeeding cessation by day 60 with in-hospital formula supplementation (n=393). RESULTS: 210 (53%) infants exclusively breastfed during the maternity stay and 183 (47%) received in-hospital formula supplementation. The most prevalent reasons mothers cited for inhospital formula supplementation were: perceived insufficient milk supply (18%), signs of inadequate intake (16%), and poor latch or breastfeeding (14%). Prevalence of not fully breastfeeding days 30–60 was 67.8% vs 36.7%, ARR 1.8 [95% CI, 1.4–2.3], in-hospital formula supplementation vs exclusively breastfed groups respectively, and breastfeeding cessation by day 60 was 32.8% vs 10.5%, ARR 2.7 [95% CI,1.7–4.5]. Odds of both adverse outcomes increased with more in-hospital formula supplementation feeds (not fully breastfeeding days 30–60, P=.003 and breastfeeding cessation, P=.011). CONCLUSIONS: Among women intending exclusively breastfed, in-hospital formula supplementation was associated with nearly 2-fold greater risk of not fully breastfeeding days 30–60 and nearly 3-fold risk of breastfeeding cessation by day 60, even after adjusting for strength of breastfeeding intentions. Strategies should be sought to avoid unnecessary in-hospital formula supplementation and to support breastfeeding when in-hospital formula supplementation is unavoidable