Recurrent NOMO1 gene deletion is a potential clinical marker in early-onset colorectal cancer and is involved in the regulation of cell migration

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC–IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial–mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.This study was supported by the health research program of the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness, PI20/01569 and PI20/0974), co-funded by FEDER funds, and Mutua Madrileña Foundation (FMM20/001). A.M.-M was supported by a predoctoral research grant from the Dr. Moraza Fundation (FMoraza18/001). P.G.V and N.G.-U were supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León. A.N.H. was supported by the National Institutes of Health K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients:results from the ColoCare Study

B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinearlinear=0.003), IL-6 (r=-0.39, plinear linear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinearlinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.</p

Familial component of early-onset colorectal cancer: opportunity for prevention

[Background]: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. [Methods]: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. [Results]: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). [Conclusion]: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.This study was funded by Instituto de Salud Carlos III through project PI20/0974 to J.P and PI19/01867 to F.B. (co-funded by European Regional Development Fund ‘A way to make Europe’); and Agència de Gestió d’Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRC 2017SGR653). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is funded by the Instituto de Salud Carlos III

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis

Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer

Copy neutral loss of heterozygosity (cnLOH) is a common event in several human malignancies—positing this as a mechanism of carcinogenesis. However, the role of cnLOH in synchronous colorectal cancer (SCRC), a unique CRC subtype, is not well understood. The aim of this study was to establish a cnLOH profile of SCRC using a single-nucleotide polymorphism array (SNP-A), and to explore associations between cnLOH and the genomic landscape of frequently mutated genes in SCRC. Among 74 paired SCRC cases, the most frequently altered regions were 16p11.2–p11.1 (59.5%) and 11p11.2–p11.12 (28.4%). Notably, the 6q11.21–q11.22 region altered by cnLOH was uniquely associated with polyclonal SCRCs (p = 0.038). Together, our analysis suggests that inactivation of tumor suppressor genes and cnLOH are rare events among SCRC cases. This study defines distinct patterns of cnLOH in SCRC, and provides initial evidence of a role for cnLOH in SCRC etiology.This work was funded by Projects PI16/01650 to JP, and PI16/01920 to RG-S, from the Spanish Ministry of Health and Consumer Affairs and FEDER, by Project 2012-0036 from the Mutua Madrileña Foundation. ANH was supported by the National Institutes of Health K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development