A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer

Objective Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. Design We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤50 years old (n = 188), a group of sporadic CRC >50 years (MSS n = 89; MSI n = 46), and a group of Lynch syndrome CRCs (n = 20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. Results Mean LINE-1 methylation levels (±SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥65% LINE-1 methylation had significantly better overall survival (p = 0.026, log rank test). Conclusions LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC

Comparative phylogeography in the Atlantic forest and Brazilian savannas: pleistocene fluctuations and dispersal shape spatial patterns in two bumblebees

Background: Bombus morio and B. pauloensis are sympatric widespread bumblebee species that occupy two major Brazilian biomes, the Atlantic forest and the savannas of the Cerrado. Differences in dispersion capacity, which is greater in B. morio, likely influence their phylogeographic patterns. This study asks which processes best explain the patterns of genetic variation observed in B. morio and B. pauloensis, shedding light on the phenomena that shaped the range of local populations and the spatial distribution of intra-specific lineages. Results: Results suggest that Pleistocene climatic oscillations directly influenced the population structure of both species. Correlative species distribution models predict that the warmer conditions of the Last Interglacial contributed to population contraction, while demographic expansion happened during the Last Glacial Maximum. These results are consistent with physiological data suggesting that bumblebees are well adapted to colder conditions. Intra-specific mitochondrial genealogies are not congruent between the two species, which may be explained by their documented differences in dispersal ability. Conclusions: While populations of the high-dispersal B. morio are morphologically and genetically homogeneous across the species range, B. pauloensis encompasses multiple (three) mitochondrial lineages, and show clear genetic, geographic, and morphological differences. Because the lineages of B. pauloensis are currently exposed to distinct climatic conditions (and elevations), parapatric diversification may occur within this taxon. The eastern portion of the state of São Paulo, the most urbanized area in Brazil, represents the center of genetic diversity for B. pauloensis

A diagnostic biopsy-adapted immunoscore predicts response to neoadjuvant treatment and selects patients with rectal cancer eligible for a watch-and-wait strategy.

PURPOSE: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait"). EXPERIMENTAL DESIGN: Biopsies from two independent cohorts (n 1 = 131, n 2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3+ and CD8+ T cells and quantified by digital pathology to determine ISB. The expression of immune-related genes post-nT was investigated (n = 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The ISB prognostic performance was further assessed in a multicentric cohort (n = 73 patients) treated by Watch-and-Wait. RESULTS: ISB positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P = 0.006). ISB high identified patients at lower risk of relapse or death compared with ISB low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; P = 0.009]. Prognostic performance of ISB for DFS was confirmed in a validation cohort. ISB was an independent parameter, more informative than pre- (P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. ISB combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort (n = 73), no relapse was observed in patients with ISB high (23.3%). CONCLUSIONS: ISB predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested