Variation to biology: optimizing functional analysis of cancer risk variants.

Research conducted over the past 15+ years has identified hundreds of common germline genetic variants associated with cancer risk, but understanding the biological impact of these primarily non-protein coding variants has been challenging. The National Cancer Institute sought to better understand and address those challenges by requesting input from the scientific community via a survey and a 2-day virtual meeting, which focused on discussions among participants. Here, we discuss challenges identified through the survey as important to advancing functional analysis of common cancer risk variants: 1) When is a variant truly characterized; 2) Developing and standardizing databases and computational tools; 3) Optimization and implementation of high-throughput assays; 4) Use of model organisms for understanding variant function; 5) Diversity in data and assays; and 6) Creating and improving large multidisciplinary collaborations.

Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report.

As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and taste, hearing loss, extreme fatigue, and "brain fog." Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented.

Overview of Research on Germline Genetic Variation in Immune Genes and Cancer Outcomes.

Since the late 19th century, the immune system has been known to play a role in cancer risk, initiation, and progression. Genome-wide association studies (GWAS) have identified hundreds of genetic risk loci for autoimmune and inflammatory diseases, yet the connection between human genetic variation and immune-mediated response to cancer treatments remains less well-explored. Understanding inherited genetic variation, with respect to germline genetic polymorphisms that affect immune system pathways, could lead to greater insights about how these processes may best be harnessed to successfully treat cancer.

Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.

Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development.

Epidemiologic Research of Rare Cancers: Trends, Resources, and Challenges.

Background: The goals of this project were to assess the status of NCI's rare cancer-focused population science research managed by the Division of Cancer Control and Population Sciences (DCCPS), to develop a framework for evaluation of rare cancer research activities, and to review available resources to study rare cancers.

Methods: Cancer types with an overall age-adjusted incidence rate of less than 20 cases per 100,000 individuals were identified using NCI Surveillance, Epidemiology and End Results (SEER) Program data. SEER data were utilized to develop a framework based on statistical commonalities.

Imaging inflammation and its resolution in health and disease: current status, clinical needs, challenges, and opportunities.

Inflammation is a normal process in our body; acute inflammation acts to suppress infections and support wound healing. Chronic inflammation likely leads to a wide range of diseases, including cancer. Tools to locate and monitor inflammation are critical for developing effective interventions to arrest inflammation and promote its resolution.

Robustness of RNA sequencing on older formalin-fixed paraffin-embedded tissue from high-grade ovarian serous adenocarcinomas.

Formalin-fixed paraffin-embedded (FFPE) tissues are among the most widely available clinical specimens. Their potential utility as a source of RNA for transcriptome studies would greatly enhance population-based cancer studies. Although preliminary studies suggest FFPE tissue may be used for RNA sequencing, the effect of storage time on these specimens needs to be determined.

Residual tissue repositories as a resource for population-based cancer proteomic studies.

Background: Mass spectrometry-based proteomics has become a powerful tool for the identification and quantification of proteins from a wide variety of biological specimens. To date, the majority of studies utilizing tissue samples have been carried out on prospectively collected fresh frozen or optimal cutting temperature (OCT) embedded specimens. However, such specimens are often difficult to obtain, in limited in supply, and clinical information and outcomes on patients are inherently delayed as compared to banked samples.

The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial Pathology Tissue Resource.

Background: Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial.

Methods: Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction.

The PLCO Biorepository: Creating, Maintaining, and Administering a Unique Biospecimen Resource.

Inclusion of biospecimens in population-based studies is an integral part of understanding disease etiology, identifying biomarkers and developing prevention and treatment strategies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial collected, processed and stored biospecimens from participants to create a biorepository of specimens which serves as a useful resource for a broad research community. PLCO collected blood samples from consented screening arm participants at six screening rounds and a buccal sample from consented control arm participants.

Robustness of Next Generation Sequencing on Older Formalin-Fixed Paraffin-Embedded Tissue.

Next Generation Sequencing (NGS) technologies are used to detect somatic mutations in tumors and study germ line variation. Most NGS studies use DNA isolated from whole blood or fresh frozen tissue. However, formalin-fixed paraffin-embedded (FFPE) tissues are one of the most widely available clinical specimens.

Using Immune Marker Panels to Evaluate the Role of Inflammation in Cancer: Summary of an NCI-sponsored Workshop.

Chronic inflammation is recognized to play a role in the development of several cancers. Past investigations of inflammation and cancer have typically been small, used varied assay platforms, and included a narrow range of analytes. Multiplex technologies have now been developed to measure larger numbers of inflammatory markers using small volumes of specimens.

Leveraging biospecimen resources for discovery or validation of markers for early cancer detection.

Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers.

SEER cancer registry biospecimen research: yesterday and tomorrow.

The National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) registries have been a source of biospecimens for cancer research for decades. Recently, registry-based biospecimen studies have become more practical, with the expansion of electronic networks for pathology and medical record reporting. Formalin-fixed paraffin-embedded specimens are now used for next-generation sequencing and other molecular techniques.

The use of biospecimens in population-based research: a review of the National Cancer Institute's Division of Cancer Control and Population Sciences grant portfolio.

Over the past two decades, researchers have increasingly used human biospecimens to evaluate hypotheses related to disease risk, outcomes and treatment. We conducted an analysis of population-science cancer research grants funded by the National Cancer Institute (NCI) to gain a more comprehensive understanding of biospecimens and common derivatives involved in those studies and identify opportunities for advancing the field. Data available for 1,018 extramural, peer-reviewed grants (active as of July 2012) supported by the Division of Cancer Control and Population Sciences (DCCPS), the NCI Division that supports cancer control and population-science extramural research grants, were analyzed.

HIV genotypes and primary drug resistance among HIV-seropositive blood donors in Brazil: role of infected blood donors as sentinel populations for molecular surveillance of HIV.

Background: There are few surveillance studies analyzing genotypes or primary (transmitted) drug resistance in HIV-infected blood donors in Brazil. The aim of this study was to characterize patterns of HIV genotypes and primary resistance among HIV-seropositive donors identified at 4 geographically dispersed blood centers in Brazil.

Methods: All HIV-infected donors who returned for counseling at the 4 REDS-II Hemocenters in Brazil from January 2007 to March 2011 were invited to participate in a case-control study involving a questionnaire on risk factors.

Electrocardiographic abnormalities in Trypanosoma cruzi seropositive and seronegative former blood donors.

Background: Blood donor screening leads to large numbers of new diagnoses of Trypanosoma cruzi infection, with most donors in the asymptomatic chronic indeterminate form. Information on electrocardiogram (ECG) findings in infected blood donors is lacking and may help in counseling and recognizing those with more severe disease.

Objectives: To assess the frequency of ECG abnormalities in T.

Ten-year incidence of Chagas cardiomyopathy among asymptomatic Trypanosoma cruzi-seropositive former blood donors.

Background: Very few studies have measured disease penetrance and prognostic factors of Chagas cardiomyopathy among asymptomatic Trypanosoma cruzi-infected persons.

Methods And Results: We performed a retrospective cohort study among initially healthy blood donors with an index T cruzi-seropositive donation and age-, sex-, and period-matched seronegatives in 1996 to 2002 in the Brazilian cities of São Paulo and Montes Claros. In 2008 to 2010, all subjects underwent medical history, physical examination, ECGs, and echocardiograms.

Lot-to-lot variability in HLA antibody screening using a multiplexed bead-based assay.

Background: Identifying antibodies to HLA (anti-HLA) by solid-phase assays is used to screen blood donors to mitigate transfusion-related acute lung injury risk. Various cutoffs for detection assays have been proposed in the literature; however, these do not take into consideration lot-to-lot variability of commercially available assays.

Study Design And Methods: Samples from 93 nontransfused males were tested using five different lots of a multiplex bead-based anti-HLA detection kit.

Antibody levels correlate with detection of Trypanosoma cruzi DNA by sensitive polymerase chain reaction assays in seropositive blood donors and possible resolution of infection over time.

Background: The clinical significance of anti-Trypanosoma cruzi low-level reactive samples is incompletely understood. Polymerase chain reaction (PCR)-positive rates and antibody levels among seropositive blood donors in three countries are described.

Study Design And Methods: Follow-up samples were collected from T.

Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy.

Background: The benefits of endoscopic testing for colorectal-cancer screening are uncertain. We evaluated the effect of screening with flexible sigmoidoscopy on colorectal-cancer incidence and mortality.

Methods: From 1993 through 2001, we randomly assigned 154,900 men and women 55 to 74 years of age either to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care.