Oral microbiome may play an important role in cancer pathogenesis. However, no study has prospectively investigated the association of the oral microbiome with subsequent risk of developing ...colorectal cancer (CRC). We conducted a nested case–control study including 231 incident CRC cases and 462 controls within the Southern Community Cohort Study with 75% of the subjects being African‐Americans. The controls were individually matched to cases based on age, ethnic group, smoking, season‐of‐study enrollment and recruitment method. Oral microbiota were assessed using 16S rRNA gene sequencing in pre‐diagnostic mouth rinse samples. Multiple bacterial taxa showed an association with CRC risk at p <0.05. Oral pathogens Treponema denticola and Prevotella intermedia were associated with an increased risk of CRC, with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.76(1.19–2.60) and 1.55(1.08–2.22), respectively, for the individuals carrying these bacteria compared to non‐carriers. In the phylum Actinobacteria, Bifidobacteriaceae was more abundant among CRC patients than among controls. In the phylum Bacteroidetes, Prevotella denticola and Prevotella sp. oral taxon 300 were associated with an increased CRC risk, while Prevotella melaninogenica was associated with a decreased risk of CRC. In the phylum Firmicutes, Carnobacteriaceae, Streptococcaceae, Erysipelotrichaceae, Streptococcus, Solobacterium, Streptococcus sp. oral taxon 058 and Solobacterium moorei showed associations with a decreased risk of CRC. Most of these associations were observed among both African‐ and European‐Americans. Most of the associations were not significant after Bonferroni correction for multiple testing, which may be conservative. Our study suggests that the oral microbiome may play a significant role in CRC etiology.
What's new?
Oral microbiome composition is of special interest in research on colorectal cancer risk, owing in part to evidence that certain oral microbes cause chronic inflammation. In this prospective investigation of participants in the Southern Community Cohort Study in the United States, multiple oral bacterial taxa were associated with risk of developing colorectal cancer. Among the taxa, two species, Treponema denticola and Prevotella intermedia, previously were described as pathogenic in the oral cavity. The findings suggest that oral microbiome composition influences colorectal cancer risk, warranting further investigation for the possible use of oral microbiota in colorectal cancer detection and prevention.
Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high ...resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.
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•A single-cell resolution atlas of human adenomas and serrated polyps•Serrated polyps arise from metaplasia as opposed to stem cell expansion•Cytotoxic immunity in serrated polyps occurs independently of hypermutation•Distinct immune microenvironments track tumor cell-differentiation states
A single-cell resolution atlas of human colorectal polyps maps out distinct paths for pre-cancer to cancer transformation, accompanied by differential immune microenvironment features.
Purpose
Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk.
...Methods
We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S
rRNA
gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk.
Results
No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families
Lachnospiraceae_XIV
,
Peptostreptococcaceae_XI
, and
Erysipelotrichaceae
and species
Parvimonas micra
was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59–0.98), 0.80 (0.66–0.97), 0.81 (0.67–0.99), and 0.83 (0.71–0.98), respectively (all
p
< 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus
Bacteroidetes_G-5
and species
Alloprevotella sp._oral_taxon_912
,
Capnocytophaga sputigena
,
Lactococcus lactis
,
Peptoniphilaceae_G-1 sp._oral_taxon_113
,
Leptotrichia sp._oral_taxon_225
, and
Fretibacterium fastidiosum
was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30–1.00), 0.36 (0.17–0.73), 0.53 (0.31–0.92), 0.43 (0.21–0.88), 0.43 (0.19–0.94), 0.57 (0.34–0.99), and 0.54 (0.31–0.94), respectively (all
p
< 0.05). Species
L. sp._oral_taxon_225
was significantly associated with decreased lung cancer risk in African Americans (OR 95% CIs 0.28 0.12–0.66;
p
= 0.00012).
Conclusion
Results from this study suggest that oral microbiota may play a role in the development of lung cancer.
Exome sequencing using next-generation sequencing technologies is a cost efficient approach to selectively sequencing coding regions of human genome for detection of disease variants. A significant ...amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment.
We performed whole exome sequencing on 22 subjects using Agilent SureSelect capture reagent and 6 subjects using Illumina TrueSeq capture reagent. We also downloaded sequencing data for 6 subjects from the 1000 Genomes Project Pilot 3 study. Using these data, we examined the quality of SNPs detected outside target regions by computing consistency rate with genotypes obtained from SNP chips or the Hapmap database, transition-transversion (Ti/Tv) ratio, and percentage of SNPs inside dbSNP. For all three platforms, we obtained high-quality SNPs outside target regions, and some far from target regions. In our Agilent SureSelect data, we obtained 84,049 high-quality SNPs outside target regions compared to 65,231 SNPs inside target regions (a 129% increase). For our Illumina TrueSeq data, we obtained 222,171 high-quality SNPs outside target regions compared to 95,818 SNPs inside target regions (a 232% increase). For the data from the 1000 Genomes Project, we obtained 7,139 high-quality SNPs outside target regions compared to 1,548 SNPs inside target regions (a 461% increase).
These results demonstrate that a significant amount of high quality genotypes outside target regions can be obtained from exome sequencing data. These data should not be ignored in genetic epidemiology studies.
Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE
) with overall and cause-specific ...mortality and examine potential effect modifiers, we obtained urinary PGE-M levels of 2927 non-cancerous adults from our previous case-control studies nested in the Shanghai Women's Health Study and Shanghai Men's Health Study, two cohort studies conducted in Shanghai, China. Mortality data and modifiable factors associated with urinary PGE-M were obtained from the parent cohort studies. Using linear regression models, we found that high urinary PGE-M levels were significantly associated with low education, heaving smoking, old age at urine collection, and abdominal obesity. Using Cox proportional hazards models, we found that increase (per standard deviation) of urinary PGE-M levels were significantly associated with overall mortality (adjusted hazard ratio = 1.19, 95% confidence interval: 1.07, 1.33) and particularly deaths from cardiometabolic diseases (adjusted hazard ratio = 1.27, 95% confidence interval: 1.11, 1.44). The increased death risks persisted across different time intervals during the follow-up and were stronger among participants who were younger than 60 (P = 0.0014 for all- cause mortality and P = 0.007 for deaths from cardiometabolic diseases) at urine collection or perhaps among those who had higher education.
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide ...association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
Molecular classification of breast cancer is an important prognostic factor. The distribution of molecular subtypes of breast cancer and their prognostic value has not been well documented in Asians.
...A total of 2,791 breast cancer patients recruited for a population-based cohort study were evaluated for molecular subtypes of breast cancer by immunohistochemical assays. Data on clinicopathological characteristics were confirmed by centralized pathology review. The average follow-up of the patients was 53.4 months. Overall and disease-free survival by molecular subtypes of breast cancer were evaluated.
The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and triple-negative subtypes were 48.6%, 16.7%, 13.7%, and 12.9%, respectively. The luminal A subtype was more likely to be diagnosed in older women (P = 0.03) and had a stronger correlation with favorable clinicopathological factors (smaller tumor size, lower histologic grade, and earlier TNM stage) than the triple-negative or HER2 subtypes. Women with triple-negative breast cancer had a higher frequency of family history of breast cancer than women with other subtypes (P = 0.048). The 5-year overall/disease-free survival percentages for the luminal A, luminal B, HER2, and triple-negative subtypes were 92.9%/88.6%, 88.6%/85.1%, 83.2%/79.1%, and 80.7%/76.0%, respectively. A similar pattern was observed in multivariate analyses. Immunotherapy was associated with improved overall and disease-free survival for luminal A breast cancer, but reduced disease-free survival (HR = 2.21, 95% CI, 1.09-4.48) for the HER2 subtype of breast cancer.
The triple-negative and HER2 subtypes were associated with poorer outcomes compared with the luminal A subtype among these Chinese women. The HER2 subtype was more prevalent in this Chinese population compared with Western populations, suggesting the importance of standardized HER2 detection and anti-HER2 therapy to potentially benefit a high proportion of breast cancer patients in China.
The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 ...whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.
Purpose
Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in ...this population, we used the whole-exome sequencing data in a population-based case–control study conducted in Shanghai, China.
Methods
We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study.
Results
Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (
P
= 3.05 × 10
−15
). Among cases, 3.7% had a
BRCA
2 pathogenic variant and 1.6% had a
BRCA1
pathogenic variant, while 2.5% had a pathogenic variant in other genes including
ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53
as well as
BARD1, BRIP,
and
RAD51D
. Patients with
BRCA
1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants.
Conclusions
This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of
BRCA2
compared to
BRCA1
. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.
Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse ...genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies.
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