non-CRC Cancer Research Articles

Variant Characterization of a Representative Large Pedigree Suggests "Variant Risk Clusters" Convey Varying Predisposition of Risk to Lynch Syndrome.

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three "variant risk clusters" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different "variant risk clusters" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.

The use of social care services by individuals aged 50 and over diagnosed with colorectal cancer in Scotland: a linked data study.

The objective of this paper is to explore how a colorectal cancer (CRC) diagnosis influences an individual’s use of social care services in Scotland. In particular, we aim to compare this use to individual’s diagnosed with other cancers and to those without a cancer diagnosis.
 We use a linked health and social care dataset of the Scottish population aged 50 and over in the financial year 2015/16. Our approach involves several methods to estimate the effect of a CRC diagnosis on social care use. Firstly, we conduct difference in means tests. Secondly, we estimate two-part models of the utilisation of social care for the CRC, other cancer and non-cancer groups. Lastly, we use propensity score matching. Models are estimated for those diagnosed during 2015/16 and for those diagnosed during 2015/16 or with an historical diagnosis.
 Preliminary results reveal that the likelihood of receipt of social care services is higher for those diagnosed with CRC compared to those without a cancer diagnosis. Further, individuals with a non-CRC cancer diagnosis are more likely to receive social care services compared to those without a cancer diagnosis, but they are less likely to receive social care compared to those with a CRC diagnosis. Further, the likelihood of care receipt for the CRC and other cancer group increases as the number of years since a cancer diagnosis increases. In terms of the number of services received, CRC patients and those with other types of cancer receive fewer services when compared to those without a cancer diagnosis.
 Our paper has demonstrated that a CRC diagnosis has a significant impact on an individual’s use of social care services. However, conditional on receiving social care, the number of services received is lower for individuals with CRC. Further research is required to understand whether the needs of those individuals are being met.

Colorectal cancer risk in association with colorectal cancer as a second malignancy in relatives: a nationwide cohort study

BackgroundIncreasing number of individuals will have first-degree relatives (FDRs) diagnosed with colorectal cancer (CRC), as a second primary malignancy (CRCa-2) after a non-CRC cancer. We aimed to estimate whether and to what extent a family history of CRCa-2 is associated with an increased CRC risk.MethodsIn this Swedish nationwide cohort study, rate ratio (RR) and cumulative incidence of CRC were estimated among 172,531 individuals with a family history of CRC as a first primary malignancy (CRCa-1) and 17,830 with a family history of CRCa-2, respectively, using individuals without cancer family history as the reference group.ResultsA cumulative incidence of CRC by age 80 was 6.3 and 5.6% for individuals with a parental and a sibling family history of CRCa-2, respectively. RRs of CRC for one FDR diagnosed with CRCa-1 and CRCa-2 were respectively 1.72 (95% CI, 1.65–1.79) and 1.50 (1.32–1.70); the latter RR was lower than the former (P = 0.0356), but no difference was observed after adjusting age of diagnosis of CRC in FDR and family relationship (P = 0.6898). Increased RRs were found to be associated with a CRCa-2 diagnosis in FDR that occured after cancers in upper aerodigestive tract, breast, prostate, kidney and nervous system.ConclusionsIndividuals who have relatives with CRCa-2 have an increased risk of CRC, but the magnitude is lower than those having relatives with CRCa-1, which is related to different ages of diagnosis of CRC in FDR and family relationships.

OUTCOMES AFTER IN-HOSPITAL CPR IN ADULT PATIENTS WITH COLORECTAL CANCER: A NATIONAL INPATIENT SAMPLE STUDY

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Recent study found that the prognosis of in-hospital cardiopulmonary resuscitation (ICPR) in cancer patients was improved but still had worse prognosis than general population. Certain cancer types were also identified as poor prognostic factors. We aim to investigate the impact of colorectal cancer (CRC), the third most common cause of cancer, in the outcomes of ICPR, which are relatively unknown. METHODS: We conducted a retrospective analysis of National Inpatient Sample database (2016-2018) including adult admissions with ICPR. International Classification of Diseases, 10th Revision, Clinical Modification procedure codes and diagnosis codes were used to identify the procedure (e.g. ICPR) and diagnosis (e.g. CRC), respectively. Primary outcome was mortality. The associated variables such as age, gender, race, insurance type, shockable arrest rhythm, severe sepsis, intubation, hypothermia protocol, palliative care encounter, and comorbidities (Age-adjusted Charlson Comorbidity Index) were analyzed and adjusted with the generalized linear model. RESULTS: A total of 67,351 adult ICPR-associated hospitalizations were identified. Among them, 7,008 records had at least one cancer diagnosis of which 13.3% (n=929) had CRC. The mortality of admissions with CRC was higher than that of non-CRC patients (82.2% vs 68.6%, adjusted odds ratio [aOR]: 1.77, [95% confidence interval {CI}: 1.61-1.80], p<1*10-9). Advanced age (≥ 65-year-old) and African Americans also had higher mortality (aOR: 1.30, p<2*10-16; aOR: 1.09, p<0.0002). Among hospitalizations with cancer diagnosis, CRC subgroup had borderline significant trend of higher mortality (aOR: 1.18, p<0.1). There was higher risk of severe sepsis in CRC subgroup than other cancer patients (aOR: 1.28, p<0.005). Utilization of palliative care of CRC-associated hospitalizations was higher (aOR: 1.30, p<0.002) compared to non-CRC patients; nevertheless, there was no significant difference between CRC and non-CRC cancer cases (p>0.8). The total charges and length of stay were lower in CRC patients but not statistically different. CONCLUSIONS: Consistent with previous studies of solid tumor patients, CRC was associated with worse ICPR survival outcome. Advanced age and African Americans were also associated with higher mortality. Among cancer patients, CRC subgroup had an unfavorable trend of higher mortality. Higher risk of severe sepsis could possibly lead to less favorable outcomes of CRC than that of other cancer subgroups. Despite the trend of worse prognosis, CRC patients did not have higher palliative care utilization than the non-CRC cancer patients. CLINICAL IMPLICATIONS: ICPR in CRC-associated hospitalization had significant higher mortality. The clinicians, patients, and the health care surrogate should understand the poor prognosis after ICPR when discussing the code status, goal of care before or after ICPR. DISCLOSURES: No relevant relationships by Tien-Chan Hsieh, source=Web Response No relevant relationships by Gin Yi Lee, source=Web Response No relevant relationships by Kaiqing Lin, source=Web Response No relevant relationships by Yee Hui Yeo, source=Web Response No relevant relationships by Guangchen Zou, source=Web Response

Tailoring Surveillance Colonoscopy in Patients With Advanced Adenomas

Patients with advanced colorectal adenomas (AAs) are directed to undergo intensive surveillance. However, the benefit derived from surveillance may be outweighed by the risk of death from non-colorectal cancer (CRC) causes, leading to uncertainty on how best to individualize follow-up. The aim of this study was to derive a risk prediction model and risk index that estimate and stratify the risk for non-CRC cancer mortality (NCM) subsequent to diagnosis and removal of AA. We conducted a retrospective cohort study of veterans ≥40 years old who had colonoscopy for diagnostic or screening indications at 13 Veterans Affairs Medical Centers between 2002 and 2009 and had 1 or more AAs. The primary outcome was NCM using a fixed follow-up time period of 5 years. Logistic regression using the lasso technique was used to identify factors independently associated with NCM, and an index based on points from regression coefficients was constructed to estimate risk of 5-year NCM. We identified 2943 veterans with AA (mean age [standard deviation] 63 [8.6] years, 98% male, 74% white), with an overall 5-year mortality of 16.7%, which was nearly all due to NCM (16.6%). Age, comorbidity burden, specific comorbid conditions, and hospitalization within the preceding year were independently associated with NCM. The risk prediction model had a goodness of fit (calibration) P value of .41 and c-statistic (discrimination) of 0.74 (95% confidence interval, 0.71-0.76). On the basis of comparable 5-year risks of NCM, the scores comprised 3 risk categories: low (score of 0-1), intermediate (score of 2-4), and high (score of ≥5), in which NCM occurred in 6.5%, 14.1%, and 33.2%, respectively. We derived a risk prediction model that identifies veterans with advanced adenomas who are at high risk of NCM within 5 years, and who are thus unlikely to benefit from further surveillance.

Analyzing non-cancer causes of death of colorectal carcinoma patients in the US population for the years 2000-2016.

ABSTRACTBackgroundColorectal cancer (CRC) treatment and patient survival improved greatly. Consequently an increased incidence of non‐cancer‐related deaths is observed. This study analyzed the causes of non‐cancer death for people suffering from CRC based on the year of diagnosis, follow‐up time, and patient's age.MethodsThe data from patients diagnosed with CRC in the years 2000–2016 were taken from the Surveillance, Epidemiology, and End Results 18 database. Patients were categorized according to: death from CRC, non‐CRC cancer, and non‐cancer. Constituent ratios and standardized mortality ratios (SMRs) were calculated to describe the death causes distribution and relative death risks.ResultsBetween 2000 and 2016, a stable and rapid drop for the original diagnosis as death cause for CRC patients was observed (70.19% to 49.35%). This was coupled to an increase in non‐cancer‐associated death reasons (23.38% to 40.00%). The most common non‐cancer death cause was heart disease, especially for elderly patients. However, deaths from accidents and adverse effects were frequent in younger CRC patients. Patients died from septicemia more often within the first follow‐up year; however, a 6‐fold increase in death from Alzheimer's disease was found for after at least 180 months follow‐up time.The SMRs of all 25 non‐cancer death causes initially decreased in all CRC subgroups, followed by an increase with follow‐up times. Gradually decreasing SMR values were observed with increasing age of CRC patients.ConclusionsThese findings could help modify and sharpen preventive measures and clinical management and raise physician's awareness to potential non‐CRC death risk factors for CRC patients.

Abstract A05: Development and clinical performance of an accurate cell-free DNA (cfDNA) methylation assay for early detection of colorectal cancer

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and its incidence is increasing in younger persons. Established CRC screening methods include fecal immunochemical testing, which requires handling of stool, and colonoscopy, which is invasive. Many persons who remain unscreened might accept a blood-based screening test, which could have profound public health impact. DNA methylation is a stable, early, and tissue-specific event in cancer development and progression. Measuring the methylation status of tumor-derived cell-free DNA in plasma could enable identification of early-stage CRC. We first developed a plasma-based methylated DNA panel for all stages of CRC (Study 1). We then validated this panel in a subsequent study with independent samples (Study 2). Methods: Differentially methylated regions (DMRs) were initially selected by analyzing tissue data from The Cancer Genome Atlas (TCGA) database. In Study 1, candidate regions were evaluated in plasma samples of 215 patients (93 CRC, 122 controls including 31 with non-advanced adenoma) using methylation-sensitive restriction enzyme qPCR (MSRE-qPCR). This training set was used for marker evaluation and construction of a prediction model. The most promising methylation markers were selected by a support vector machine (SVM)-based machine learning classifier using a random forest algorithm. In Study 2, the selected markers were validated in an independent validation set of 724 samples collected in Spain, Ukraine, the UK, and the US (152 CRC, 622 controls including 148 with non-advanced adenoma and 52 with non-CRC cancer). Results: Tissue data analysis yielded 180 potential DMRs. In Study 1, a panel consisting of the top 12 methylation markers was selected. In Study 2, the prediction model based on this panel correctly classified 117/152 CRC (77%) patients. Sensitivity improved with CRC stage, ranging from 71% (25/35) for stage I, 76% (37/49) for stage II, 77% (37/48) for stage III, to 100% (14/14) for stage IV. Specificity of the model was 88% (544/622). Among non-CRC cancer cases, specificity was 83% overall (73% [19/26] for lung cancer and 92% [24/26] for breast cancer). Conclusions: We developed a prediction model based on a novel plasma 12-marker methylation panel that demonstrated highly promising test performance characteristics for early-stage CRC detection in a validation study using independent samples. This method could serve as the basis for a highly accurate and minimally invasive blood-based CRC screening test. Citation Format: Kristi Kruusmaa, Marko Bitenc, Walter Pulverer, Andreas Weinhaeusel, José Luis Rodrigo Agudo, Andrés Barrientos Delgado, Andrés Sánchez Yagüe, José Manuel Rodríguez Laiz, Marko Chersicola, Primož Knap, Silvia Schönthaler, Uri Ladabaum. Development and clinical performance of an accurate cell-free DNA (cfDNA) methylation assay for early detection of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A05.

Familial and non-familial risk factors associated with incidence of colorectal cancer in young and middle-aged persons in Western Australia

AimsThe aim of this study was to examine factors including family history, medical history and comorbidities associated with the risk of colorectal cancer (CRC) in young (18–49 years) and middle-age (50–69 years) individuals. MethodsState records were used to identify individuals born in Western Australia between 1945 and 1996, and their first-degree relatives. Individuals in the cohort and their relatives were linked to State cancer registry, hospital and mortality data to identify diagnoses of CRC and other risk factors. The associations between CRC and identified risk factors were examined using multivariable logistic regression. ResultsFor both young and middle-aged patients, family history of CRC, and a history of smoking, inflammatory bowel disease, liver disease and non-CRC cancer were associated with a significant increase in odds of CRC. In middle-aged patients, having a colonoscopy in the previous 10 years was associated with a reduced odds of CRC regardless of the detection of polyps. However, in young patients only the absence of polyps as confirmed by colonoscopy was associated with a decreased risk of CRC (OR: 0.38, 95%CI: 0.26 – 0.54, p < 0.001). ConclusionsMany of the risk factors associated with CRC were similar in young and middle-aged persons, and should be used to identify high risk young patients for screening. The association between colonoscopy and polyps with CRC was modified by age, likely as the result of routine screening in middle-aged patients.

PO484 Lived Experience of Young Smokers With Respect to Smoking Ban on University Campus

The aim of this study was to examine factors including family history, medical history and comorbidities associated with the risk of colorectal cancer (CRC) in young (18–49 years) and middle-age (50–69 years) individuals.State records were used to identify individuals born in Western Australia between 1945 and 1996, and their first-degree relatives. Individuals in the cohort and their relatives were linked to State cancer registry, hospital and mortality data to identify diagnoses of CRC and other risk factors. The associations between CRC and identified risk factors were examined using multivariable logistic regression.For both young and middle-aged patients, family history of CRC, and a history of smoking, inflammatory bowel disease, liver disease and non-CRC cancer were associated with a significant increase in odds of CRC. In middle-aged patients, having a colonoscopy in the previous 10 years was associated with a reduced odds of CRC regardless of the detection of polyps. However, in young patients only the absence of polyps as confirmed by colonoscopy was associated with a decreased risk of CRC (OR: 0.38, 95%CI: 0.26 – 0.54, p < 0.001).Many of the risk factors associated with CRC were similar in young and middle-aged persons, and should be used to identify high risk young patients for screening. The association between colonoscopy and polyps with CRC was modified by age, likely as the result of routine screening in middle-aged patients.

Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force.

Cancer is the second leading cause of death in the United States. To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk. MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews. Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria. Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another. In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n= 103787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n= 72926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n= 14033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n= 47464). Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited. In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation. Agency for Healthcare Research and Quality.

The Hidden Value of Upper Endoscopy: A “Teachable Moment” for Colorectal Cancer Screening

The Hidden Value of Upper Endoscopy: A ‘‘Teachable Moment’’ for Colorectal Cancer Screening Stacy B. Menees, A.M. Fendrick, Ruth Carlos, James Scheiman Background: Nearly half of Americans do not undergo colorectal cancer (CRC) screening as recommended by professional organizations. Those individuals inadequately screened for CRC who are referred for open access esophagoduodenoscopy (EGD) represent an opportunity for gastroenterologists to provide education regarding the benefits of CRC screening and ultimately enhance adherence rates. CRC screening rates for eligible individuals undergoing upper access EGD has not been established. Aims: 1. Determine the rate of CRC screening among a cohort of patients undergoing direct access EGD for whom screening is recommended; 2. Determine predictors of CRC screening in this population. Methods: A retrospective chart review of 1076 consecutive patients undergoing open access EGD from January 2003 to June 2004 was undertaken at a large Midwestern academic medical center to determine compliance with CRC screening recommendations. Only patients followed by a primary care provider (PCP) at this same institution for at least one year were eligible. Demographic, insurance coverage, duration of primary care physician relationship and other preventive care services were analyzed to determine predictors of CRC screening. Results: Of the 247 individuals undergoing EGD who met inclusion criteria and were eligible for CRC screening (57% women, 84% Caucasian, mean age 60 years, mean primary physician relationship 5.5 years), 68% were up to date with CRC screening. Significant predictors of screening included younger age (aged 55-59 and 60-64 (OR Z 3.01, 95% CI 2.22,7.42; OR Z 4.04, 95%CI 1.56,10.19), adherence to non-CRC cancer screening (OR Z 3.70, 95%CI 1.49,9.20) and a PCP relationship of 9 years or greater (OR Z 2.34, 95% CI 1.22,4.05). Female gender was a significant negative predictor of CRC screening (OR Z 0.38, 95%CI 0.18,0.80). Conclusion: At the time of open access EGD, one-third of patients who would benefit from CRC screening were not compliant with recommended guidelines. Male gender, younger age, longer doctor-patient relationships, and compliance with preventive health behaviors were associated with CRC screening. The EGD experience – especially for women may represent a ‘‘teachable moment’’ to Abstracts