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Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer.

ABSTRACT: Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa miRNA profiles. We evaluate miRNAs with disease stage and survival after adjusting for age, study center, sex, MSI status, and AJCC stage. These miRNAs were further evaluated with RNA-Seq data to identify miRNA::mRNA associations that may provide insight into the functionality of miRNAs. Eleven miRNAs were associated with advanced disease stage among colon cancer patients (Q value = 0.10). Eight infrequently expressed miRNAs influenced survival if highly expressed in overall CRC. Of these, five increased likelihood of dying if they were highly expressed, i.e. miR-124-3p, miR-143-5p, miR-145-3p, miR31-5p, and miR-99b-5p, while three were associated with better survival if highly expressed, i.e. miR-362-5p, miR-374a-5p, and miR-590-5p. Thirteen miRNAs infrequently expressed in colon-specific carcinoma tissue were associated with CRC survival if highly expressed. Evaluation of miRNAs::mRNA associations showed that mRNA expression influenced by infrequently expressed miRNA contributed to networks and pathways shown to influence disease progression and prognosis. Our large study enabled us to examine the implications of infrequently expressed miRNAs after removal of background noise. These results require replication in other studies. Confirmation of our findings in other studies could lead to important markers for prognosis.

SUBMITTER: Slattery ML

PROVIDER: S-EPMC5663559 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer.

Slattery Martha L ML Pellatt Andrew J AJ Lee Frances Y FY Herrick Jennifer S JS Samowitz Wade S WS Stevens John R JR Wolff Roger K RK Mullany Lila E LE

Oncotarget 20170803 48

Half of miRNAs expressed in colorectal tissue are expressed < 50% of the population. Many infrequently expressed miRNAs have low levels of expression. We hypothesize that less frequently expressed miRNAs, when expressed at higher levels, influence both disease stage and survival after diagnosis with colorectal cancer (CRC); low levels of expression may be background noise. We examine 304 infrequently expressed miRNAs in 1893 population-based cases of CRC with paired carcinoma and normal mucosa m ...[more]

PMID: 29137387

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Project description:We have previously shown that commonly expressed miRNAs influenced tumor molecular phenotype in colorectal cancer. We hypothesize that infrequently expressed miRNAs, when showing higher levels of expression, help to define tumor molecular phenotype. In this study, we examine 304 miRNAs expressed in at least 30 individuals, but in <50% of the population and with a mean level of expression above 1.0 relative florescent unit. We examine associations in 1893 individuals who have the tumor molecular phenotype data as well as miRNA expression levels for both carcinoma and normal colorectal tissue. We compare miRNAs uniquely associated with tumor molecular phenotype to the RNAseq data to identify genes associated with these miRNAs. This information is used to further identify unique pathways associated with tumor molecular phenotypes of TP53-mutated, KRAS-mutated, CpG island methylator phenotype and microsatellite instability tumors. Thirty-seven miRNAs were uniquely associated with TP53-mutated tumors; 30 of these miRNAs had higher level of expression in TP53-mutated tumors, while seven had lower levels of expression. Of the 34 miRNAs associated with CpG island methylator phenotype-high tumors, 16 were more likely to have a CpG island methylator phenotype-high tumor and 19 were less likely to be CpG island methylator phenotype-high. For microsatellite instability, 13 of the 22 infrequently expressed miRNAs were significantly less likely to be expressed in microsatellite unstable tumors. KRAS-mutated tumors were not associated with any miRNAs after adjustment for multiple comparisons. Of the dysregulated miRNAs, 17 were more likely to be TP53-mutated tumors while simultaneously being less likely to be CpG island methylator phenotype-high and/or microsatellite instability tumors. Genes regulated by these miRNAs were involved in numerous functions and pathways that influence cancer risk and progression. In summary, some infrequently expressed miRNAs, when expressed at higher levels, appear to have significant biological meaning in terms of tumor molecular phenotype and gene expression profiles.

Project description:ImportanceAlthough high dietary fiber intake has been associated with a lower risk of colorectal cancer (CRC), it remains unknown whether fiber benefits CRC survivors.ObjectiveTo assess the association of postdiagnostic fiber intake with mortality.Design, setting, and participantsA total of 1575 health care professionals with stage I to III CRC were evaluated in 2 prospective cohorts, Nurses' Health Study and Health Professionals Follow-up Study. Colorectal cancer-specific and overall mortality were determined after adjusting for other potential predictors for cancer survival. The study was conducted from December 23, 2016, to August 23, 2017.ExposuresConsumption of total fiber and different sources of fiber and whole grains assessed by a validated food frequency questionnaire between 6 months and 4 years after CRC diagnosis.Main outcomes and measuresHazard ratios (HRs) and 95% CIs of CRC-specific and overall mortality after adjusting for other potential predictors for cancer survival.ResultsOf the 1575 participants, 963 (61.1%) were women; mean (SD) age was 68.6 (8.9) years. During a median of 8 years of follow-up, 773 deaths were documented, including 174 from CRC. High intake of total fiber after diagnosis was associated with lower mortality. The multivariable HR per each 5-g increment in intake per day was 0.78 (95% CI, 0.65-0.93; P = .006) for CRC-specific mortality and 0.86 (95% CI, 0.79-0.93; P < .001) for all-cause mortality. Patients who increased their fiber intake after diagnosis from levels before diagnosis had a lower mortality, and each 5-g/d increase in intake was associated with 18% lower CRC-specific mortality (95% CI, 7%-28%; P = .002) and 14% lower all-cause mortality (95% CI, 8%-19%; P < .001). According to the source of fiber, cereal fiber was associated with lower CRC-specific mortality (HR per 5-g/d increment, 0.67; 95% CI, 0.50-0.90; P = .007) and all-cause mortality (HR, 0.78; 95% CI, 0.68-0.90; P < .001); vegetable fiber was associated with lower all-cause mortality (HR, 0.83; 95% CI, 0.72-0.96; P = .009) but not CRC-specific mortality (HR, 0.82; 95% CI, 0.60-1.13; P = .22); no association was found for fruit fiber. Whole grain intake was associated with lower CRC-specific mortality (HR per 20-g/d increment, 0.72; 95% CI, 0.59-0.88; P = .002), and this beneficial association was attenuated after adjusting for fiber intake (HR, 0.77; 95% CI, 0.62-0.96; P = .02).Conclusions and relevanceHigher fiber intake after the diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality. Increasing fiber consumption after diagnosis may confer additional benefits to patients with CRC.

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Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer.

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Infrequently expressed miRNAs influence survival after diagnosis with colorectal cancer.

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