Update of penetrance estimates in Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. METHODS: A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. RESULTS: Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. CONCLUSIONS: These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Quantitative Pathologic Analysis of Digitized Images of Colorectal Carcinoma Improves Prediction of Recurrence-Free Survival.

BACKGROUND & AIMS: To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis. METHODS: A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938). RESULTS: There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs. CONCLUSIONS: QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.

Cancer Risk C (CR-C), a functional genomics test is a sensitive and rapid test for germline mismatch repair deficiency.

PURPOSE: Heritable pathogenic variants in the DNA mismatch repair (MMR) pathway cause Lynch syndrome, a condition that significantly increases risk of colorectal and other cancers. At least half of individuals tested using gene panel sequencing have a variant of uncertain significance or no variant identified leading to no diagnosis. To fill this diagnostic gap, we developed Cancer Risk C (CR-C), a flow variant assay test. METHODS: In response to treatment with an alkylating agent, individual assays of the nuclear translocation of MLH1, MSH2, BARD1, PMS2, and BRCA2 proteins and the nuclear phosphorylation of the ATM and ATR proteins distinguished pathogenic/likely pathogenic (P/LP) from benign/likely benign variants in MMR genes. RESULTS: A risk classification score based on MLH1, MSH2, and ATR assays was 100% sensitive and 98% specific. Causality of MMR P/LP variants was shown through gene editing and rescue. In individuals with suspected Lynch syndrome but no P/LP, CR-C identified most (73%) as having germline MMR defects. Direct comparison of CR-C on matched blood samples and lymphoblastoid cell lines yielded comparable results (r2 > 0.9). CONCLUSION: For identifying germline MMR defects, CR-C provides augmentation to traditional panel sequencing through greater accuracy, shorter turnaround time (48 hours), and performance on blood with minimal sample handling.

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution's internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant's disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing.

PURPOSE: We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR). METHODS: Participants (n = 2,535) with hypercholesterolemia and/or colon polyps underwent targeted sequencing of 68 genes and 14 single-nucleotide variants. Penetrance was estimated based on presence of relevant traits in the electronic health record (EHR). Outcomes occurring within 1-year of RoR were ascertained by EHR review. Analyses were stratified by tier 1 and non-tier 1 disorders. RESULTS: Actionable findings were present in 122 individuals and results were disclosed to 98. The average penetrance for tier 1 disorder variants (67%; n = 58 individuals) was higher than in non-tier 1 variants (46.5%; n = 58 individuals). After excluding 45 individuals (decedents, nonresponders, known genetic diagnoses, mosaicism), ≥1 outcomes were noted in 83% of 77 participants following RoR; 78% had a process outcome (referral to a specialist, new testing, surveillance initiated); 68% had an intermediate outcome (new test finding or diagnosis); 19% had a clinical outcome (therapy modified, risk reduction surgery). Risk reduction surgery occurred more often in participants with tier 1 than those with non-tier 1 variants. CONCLUSION: Relevant phenotypic traits were observed in 57% whereas a clinical outcome occurred in 19% of participants with actionable genomic variants in the year following RoR.

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

BACKGROUND: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. METHODS: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). RESULTS: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; P = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; P = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; P = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; P = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; P = 0.68). CONCLUSIONS: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. IMPACT: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.

Integrating Genomic Screening into Primary Care: Provider Experiences Caring for Latino Patients at a Community-Based Health Center.

INTRODUCTION: Minority communities have had limited access to advances in genomic medicine. Mayo Clinic and Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, partnered to assess the feasibility of offering genomic screening to Latino patients receiving care at a community-based health center. We examined primary care provider (PCP) experiences reporting genomic screening results and integrating those results into patient care. METHODS: We conducted open-ended, semi-structured interviews with PCPs and other members of the health care team charged with supporting patients who received positive genomic screening results. Interviews were recorded, transcribed, and analyzed thematically. RESULTS: Of the 500 patients who pursued genomic screening, 10 received results indicating a genetic variant that warranted clinical management. PCPs felt genomic screening was valuable to patients and their families, and that genomic research should strive to include underrepresented minorities. Providers identified multiple challenges integrating genomic sequencing into patient care, including difficulties maintaining patient contact over time; arranging follow-up medical care; and managing results in an environment with limited genetics expertise. Providers also reflected on the ethics of offering genomic sequencing to patients who may not be able to pursue diagnostic testing or follow-up care due to financial constraints. CONCLUSIONS: Our results highlight the potential benefits and challenges of bringing advances in precision medicine to community-based health centers serving under-resourced populations. By proactively considering patient support needs, and identifying financial assistance programs and patient-referral mechanisms to support patients who may need specialized medical care, PCPs and other health care providers can help to ensure that precision medicine lives up to its full potential as a tool for improving patient care.

Experiences of Latino Participants Receiving Neutral Genomic Screening Results: A Qualitative Study.

PURPOSE: The aim of the study was to characterize experiences of Latino participants receiving genomic screening results. METHODS: Participants were recruited at a federally qualified health center in the USA. In-person, semi-structured interviews were conducted in either Spanish or English by a bilingual, bicultural interviewer. Questions focused on motivations for pursuing genomic sequencing, concerns about receiving genomic screening results, and perceived benefits of receiving genomic information. Interviews were audio-recorded, transcribed, and translated. RESULTS: Fifty individuals completed an interview; 39 were conducted in Spanish. Participants described mixed motivations for pursuing genomic screening. Participants viewed the benefits of genomic screening in relation to not only their personal health but to the health of their families and their communities. Participants tended to have few concerns about genomic screening. Those concerns related to potential loss of privacy, misuses of genomic information, and the possibility of receiving distressing results. Some participants had misunderstandings about the scope of the test and the potential implications of their results. Most felt it was better to know about a genetic predisposition to disease than to remain uninformed. Participants felt that genomic screening was worthwhile. DISCUSSION: This is one of the first studies to examine the experiences of Latino individuals receiving genomic screening results. Our results suggest that many Latino patients in the US see value in genomic screening and have limited concerns about its potential to cause harm. These results inform ongoing efforts to increase the availability of genomic medicine to underrepresented populations and add to our understanding of sociocultural drivers in the adoption of precision medicine.

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome.

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.

Increasing access to individualized medicine: a matched-cohort study examining Latino participant experiences of genomic screening.

PURPOSE: Multiple efforts are underway to increase the inclusion of racial minority participants in genomic research and new forms of individualized medicine. These efforts should include studies that characterize how individuals from minority communities experience genomic medicine in diverse health-care settings and how they integrate genetic knowledge into their understandings of health-care needs. METHODS: As part of a large, multisite genomic sequencing study, we surveyed individuals to assess their decision to pursue genomic risk evaluation. Participants included Latino patients recruited at Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, and non-Latino patients recruited at a large academic medical center (Mayo Clinic in Rochester, MN). Both groups agreed to receive individualized genomic risk assessments. RESULTS: Comparisons between cohorts showed that Latino respondents had lower levels of decisional conflict about pursuing genomic screening but generally scored lower on genetic knowledge. Latino respondents were also more likely to have concerns about the misuse of genomic information, despite both groups having similar views about the value of genomic risk evaluation. CONCLUSION: Our results highlight the importance of evaluating sociocultural factors that influence minority patient engagement with genomic medicine in diverse health-care settings.

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.

A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study.

Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.

Exploratory Genome-Wide Interaction Analysis of Nonsteroidal Anti-inflammatory Drugs and Predicted Gene Expression on Colorectal Cancer Risk.

BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. METHODS: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. RESULTS: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10-4), KRT16 (PG×E = 2.3 × 10-4), CD14 (PG×E = 9.38 × 10-4), and CYP27A1 (PG×E = 1.44 × 10-3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10-5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. CONCLUSIONS: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. IMPACT: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Returning genomic results in a Federally Qualified Health Center: the intersection of precision medicine and social determinants of health.

PURPOSE: This report describes the return of sequencing results to low-income Latino participants recruited through a Federally Qualified Health Center (FQHC). We describe challenges in returning research results secondary to social determinants of health and present lessons learned to guide future genomic medicine implementation studies in low-resource settings. METHODS: Five hundred Latino adults (76% women) consented to research sequencing for a predetermined panel of actionable genes. Providers and staff from the FQHC were engaged to align processes with the practice and a community advisory board grounded the project in the local community. RESULTS: A pathogenic/likely pathogenic variant was present in 10 participants (2%). Challenges in return of results included the time lag (582 ± 53 days) between enrollment and returning actionable results, difficulty reaching participants, missed appointments, low health literacy, lack of health insurance, and reconciling results with limited information on family history. Return of one actionable result was deferred due to acute emotional distress secondary to recent traumatic life events. CONCLUSION: The social determinants of health influence the implementation of genomic medicine in low-income populations in low-resource settings. Considering nonbiological factors that contribute to disparities will be necessary to better appreciate how genomic medicine may fit within the context of health equity.

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.

Potential impact of family history-based screening guidelines on the detection of early-onset colorectal cancer.

BACKGROUND: Initiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC. METHODS: The authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied. RESULTS: Family history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis. CONCLUSIONS: Of CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.