Whole-Genome Sequencing in Healthy People Lindor, Noralane M.; Thibodeau, Stephen N.; Burke, Wylie
Mayo Clinic proceedings,
01/2017, Volume:
92, Issue:
1
Journal Article
Peer reviewed
Open access
Recent technological advances have radically changed genetic testing from an expensive and burdensome undertaking to a rapid and less costly option for many purposes. The utility of “next-generation” ...sequencing has been found to establish the diagnosis for hundreds of genetic disorders, to assess pharmacogenomic variants, and to identify treatable targets within malignant neoplasms. The ready availability of genomic information has led to the question of whether there would be clinical benefit of sequencing the genome of individuals who are not seeking a diagnosis, that is, genomic screening in generally healthy people, to provide anticipatory insights for their health care. Little research has been conducted in this area. We examine the considerable unresolved scientific and ethical issues encountered when considering whole-genome sequencing of healthy people.
Women with a germline BRCA1 or BRCA2 mutation or a hereditary predisposition for breast and ovarian cancer have substantial risk of breast or ovarian cancer relative to the general US population. ...Health care professionals can be instrumental in identifying women at increased risk through obtaining a comprehensive family history and becoming familiar with family history characteristics associated with hereditary predisposition for breast and ovarian cancer. BRCA carriers and women at very high risk benefit from multidisciplinary, individualized medical evaluation and risk management. We conducted a search of MEDLINE from 1989 through 2010 for the terms BRCA1, BRCA2, breast cancer, ovarian cancer, risk assessment , and genetic testing . We reviewed abstracts and relevant randomized and prospective studies that included very high-risk patient groups and BRCA mutation carriers. Herein, we review the role of genetic consultation and BRCA testing and the comprehensive, multisystem recommendations for risk management. A multidisciplinary approach offers the ability to educate those at very high risk about cancer prevention, reduce cancer risk, maximize early detection of breast and ovarian cancer, and improve survival.
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.
Data supporting initiating screening at an earlier age based on family history as a strategy for the detection and prevention of early‐onset colorectal cancer (CRC) are limited. In a population‐based, case‐control study of individuals aged 40 to 49 years, the authors report that 1 in 4 meet guideline criteria for earlier screening, and that nearly all of those who meet these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per guidelines.
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.
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.
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.
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.
We estimated penetrance of actionable genetic variants and assessed near-term outcomes following return of results (RoR).
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.
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.
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.
Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, ...genetic, and environmental risk factors to enhance prevention.
A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases (
= 4,445) and controls (
= 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (
= 12,052) and clinic-based (
= 5,584) relatives with no cancer history at recruitment to assess model calibration expected/observed rate ratio (E/O) and discrimination area under the receiver-operating-characteristic curve (AUC).
The E/O 95% confidence interval (CI) for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women.
Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model.
Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.
Background & Aims We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1 , MSH2 , and MSH6 based on personal and family history of cancer. ...Methods Data were analyzed from 4539 probands tested for mutations in MLH1 , MSH2 , and MSH6 . A multivariable polytomous logistic regression model (PREMM1,2,6 ) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Results Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1 , 250 in MSH2 , and 71 in MSH6 ). The PREMM1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals CIs): male sex (1.9; 1.5–2.4), a CRC (4.3; 3.3–5.6), multiple CRCs (13.7; 8.5–22), endometrial cancer (6.1; 4.6–8.2), and extracolonic cancers (3.3; 2.4–4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82–0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83–0.92) for MSH2 , and 0.81 (95% CI, 0.69–0.93) for MSH6 ; in validation, they were 0.88 for the overall cohort (95% CI, 0.86–0.90) and the population-based cases (95% CI, 0.83–0.92). Conclusions We developed the PREMM1,2,6 model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1 , MSH2 , and MSH6 . This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that ...dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk.
We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance.
Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men.
Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.
Mutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome (RTS). A subset of RTS patients is predisposed to cancer and is sensitive to DNA damaging agents. The enhanced sensitivity ...of cells from RTS patients correlates with the accumulation of transcriptionally active nuclear p53. We found that in untreated normal human cells these two nuclear proteins, p53 and RECQL4, instead colocalize in the mitochondrial nucleoids. RECQL4 accumulates in mitochondria in all phases of the cell cycle except S phase and physically interacts with p53 only in the absence of DNA damage. p53-RECQL4 binding leads to the masking of the nuclear localization signal of p53. The N-terminal 84 amino acids of RECQL4 contain a mitochondrial localization signal, which causes the localization of RECQL4-p53 complex to the mitochondria. RECQL4-p53 interaction is disrupted after stress, allowing p53 translocation to the nucleus. In untreated normal cells RECQL4 optimizes de novo replication of mtDNA, which is consequently decreased in fibroblasts from RTS patients. Wild-type RECQL4-complemented RTS cells show relocalization of both RECQL4 and p53 to the mitochondria, loss of p53 activation, restoration of de novo mtDNA replication and resistance to different types of DNA damage. In cells expressing Δ84 RECQL4, which cannot translocate to mitochondria, all the above functions are compromised. The recruitment of p53 to the sites of de novo mtDNA replication is also regulated by RECQL4. Thus these findings elucidate the mechanism by which p53 is regulated by RECQL4 in unstressed normal cells and also delineates the mitochondrial functions of the helicase.
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