The association between age at breast cancer diagnosis and prevalence of pathogenic variants.

PURPOSE: Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2. METHODS: We analyzed multi-gene panel testing results (09/2013-12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry. RESULTS: An association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64-4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84-2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08-1.37) and CHEK2 (OR 1.34, 95% CI 1.21-1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98-1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13-2.56) and BRCA2 (OR 1.25, 95% CI 1.16-1.35). CONCLUSIONS: Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.

Individual patient-centered target-driven intervention to improve clinical outcomes of diabetes, health literacy, and self-care practices in Nepal: A randomized controlled trial.

Purpose: To examine the effectiveness of a culturally and linguistically appropriate, patient-centered, target-driven lifestyle intervention with video education training in improving clinical outcomes, health literacy, and diabetic self-care practices in newly diagnosed patients in Nepal. Methods: A total of 110 participants with newly and consequently diagnosed Type 2 were randomly allocated into intervention (mean age = 45 ± 9.7 years) and control (mean age = 47 ± 12.5 years) groups. Intervention group participants were trained on a culturally and linguistically appropriate diabetic video education program and were given a customized dietary and physical activity plan with specific targets to practice at home. Participants' compliance was monitored weekly via telephone calls. Both groups received the usual treatment from their doctor and were followed up after three months. Outcome measures included changes in: i. diabetic health literacy, diet, and physical activity measured using self-reported questionnaires; and ii. blood glucose (glycated hemoglobin, HbA1c), cholesterol, blood pressure, body mass index, and visual acuity. Clinical outcome measures were blinded from randomization and intervention allocation. Results: After three months, HbA1c decreased to 6.1% from the baseline value of 7.2% in the intervention group compared to 6.6% in the control group from the baseline value of 7.1% (p <0.05). The intervention group had mean total cholesterol and low-density lipoprotein of 174 and 95.5 mg/dL, which were significantly lower than 186 and 107.5 mg/dL in the control group. Daily white rice consumption decreased by 36.5% in the intervention vs. 4% in the control group (p <0.05). After three months, the intervention group participants exercised more than the control group (p <0.05). All intervention group participants self-initiated retinal screening checks since the baseline visit among which 13% showed early diabetic retinopathy signs compared to 0% in the control group. Health literacy improvement in the intervention group was found to be sustained after three months too. Conclusions: A culturally appropriate, target-driven lifestyle intervention with video education training is effective in improving clinical outcomes, health literacy, and self-care practice in newly diagnosed diabetic patients in Nepal, i.e., at a time period when effective diabetes control is vital to prevent further complications. The training intervention could be rolled out nationwide in order to reduce the risk of diabetic-related complications and improve people's quality of life and productivity.

Mediation analysis of multiple mediators with incomplete omics data.

There is an increasing interest in using multiple types of omics features (e.g., DNA sequences, RNA expressions, methylation, protein expressions, and metabolic profiles) to study how the relationships between phenotypes and genotypes may be mediated by other omics markers. Genotypes and phenotypes are typically available for all subjects in genetic studies, but typically, some omics data will be missing for some subjects, due to limitations such as cost and sample quality. In this article, we propose a powerful approach for mediation analysis that accommodates missing data among multiple mediators and allows for various interaction effects. We formulate the relationships among genetic variants, other omics measurements, and phenotypes through linear regression models. We derive the joint likelihood for models with two mediators, accounting for arbitrary patterns of missing values. Utilizing computationally efficient and stable algorithms, we conduct maximum likelihood estimation. Our methods produce unbiased and statistically efficient estimators. We demonstrate the usefulness of our methods through simulation studies and an application to the Metabolic Syndrome in Men study.

Pancreatic Ductal Carcinoma Risk Associated With Hereditary Cancer-Risk Genes.

BACKGROUND: Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined and are potentially biased because of the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings. METHODS: This is a retrospective analysis of 676 667 individuals, 2445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013 and 2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC because of pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal and/or family cancer history, and ancestry. RESULTS: Overall, 11.1% of patients with PDAC had a PV. Statistically significantly elevated PDAC risk (2-sided P < .05) was observed for CDK2NA (p16INK4a) (OR = 8.69, 95% CI = 4.69 to 16.12), ATM (OR = 3.44, 95% CI = 2.58 to 4.60), MSH2 (OR = 3.17, 95% CI = 1.70 to 5.91), PALB2 (OR = 3.09, 95% CI = 2.02 to 4.74), BRCA2 (OR = 2.55, 95% CI = 1.99 to 3.27), and BRCA1 (OR = 1.62, 95% CI = 1.07 to 2.43). CONCLUSIONS: This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly because of adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer.

Multigene assessment of genetic risk for women for two or more breast cancers.

PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥ 2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53-1.79, p = 7.2 × 10-33) and synchronous (OR 1.33, 95% CI 1.19-1.50, p = 2.4 × 10-6) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥ 2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.

Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.

BACKGROUND: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs). METHODS: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). RESULTS: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non-English-speaking. The genetic test results were as follows: 7% had a high-risk PV, 6% had a moderate-risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of "never," "rarely," or only "sometimes" reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high- and moderate-risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High- and moderate-risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. CONCLUSIONS: In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. LAY SUMMARY: Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate-risk pathogenic variants (mutations) and among carriers of variants of uncertain significance. This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% "never," "rarely," or only "sometimes" reacted negatively to results. Somewhat higher uncertainty and distress were identified among carriers of high- and moderate-risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result. Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results.

Family history of breast cancer in men with non-BRCA male breast cancer: implications for cancer risk counseling.

PURPOSE: The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2. METHODS: We conducted an unmatched case-control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing. RESULTS: Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR 4.7; 95% CI 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR 7.8; 95% CI 5.2, 11.6), for probands and FDR diagnosed at age < 45 years (OR 6.9; 95% CI 3.9, 12.4), and for family history of MBC (OR 17.9; 95% CI 7.6, 42.1). Findings were confirmed in a sensitivity analysis of MBC cases who tested negative on a 25-gene pan-cancer panel. CONCLUSIONS: MBC patients without mutations in BRCA1/2 have significantly higher odds of a family history of breast cancer, suggesting the existence of unidentified MBC susceptibility alleles.

Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing.

BACKGROUND: Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA). METHODS: Sequencing and LR analysis were conducted in a consecutive series of 376,159 individuals who received clinical testing with a hereditary pan-cancer gene panel from September 2013 through May 2017. NGS dosage analysis was used to evaluate potential deletions or duplications, with controls in place to exclude pseudogene reads. Samples positive for a putative LR based on NGS were confirmed using a comprehensive approach that included targeted microarray-CGH and/or MLPA analysis, with further examination as needed to ascertain the nature of the LR. RESULTS: A total of 3461 LRs were identified and classified as a deleterious mutation (DM), suspected deleterious mutation (SDM) or variant of uncertain significance. Pathogenic LRs (DM/SDM) accounted for the majority of LRs (67.7%), the largest proportion of which were deletions (86.1%), followed by duplications (11.3%), insertions (1.8%), triplications (0.5%), and inversions (0.3%). Several cases presented illustrate that the laboratory approach employed here can ensure consistent identification and accurate characterization of LRs. In the absence of this comprehensive testing strategy, 9% of LRs identified in this testing population might have been missed, potentially leading to inappropriate medical management in as many as 210 individuals referred for hereditary cancer testing. CONCLUSIONS: These data show that copy number analysis using NGS coupled with confirmatory testing reliably detects and characterizes LRs. Further, LRs comprise a substantial proportion (7.2%) of pathogenic variants identified by the test. A robust and accurate LR identification strategy is an essential component of a high-quality genetic testing program, enabling clinicians to optimize patient medical management decisions.

Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits.

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.

Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk.

PURPOSE: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations. PATIENTS AND METHODS: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). RESULTS: Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. CONCLUSION: In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.

PurposePanel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germ-line mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history.MethodsWe sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for familial pancreatic cancer (FPC), while the remaining were familial, but not FPC.ResultsThirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2.ConclusionMultiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status and will inform genetic risk counseling for families.

Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories.

Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016. The majority of individuals (92.8%) met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) and/or Lynch syndrome (LS). Overall, 17,340 PVs were identified in 17,000 (6.7%) of the tested individuals. The PV positive rate was 9.8% among individuals with a personal cancer history, compared to 4.7% in unaffected individuals. PVs were most common in BRCA1/2 (42.2%), other breast cancer (BR) genes (32.9%), and the LS genes (13.2%). Half the PVs identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2. Similarly, half of PVs identified in individuals who met only LS testing criteria were in non-LS genes. These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single-syndrome testing.

Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel.

Next Generation Sequencing (NGS) multigene panels, which are routinely used to assess hereditary cancer risk, can detect both inherited germline variants and somatic variants in cancer-risk genes. We evaluated the frequency and distribution of likely somatic Pathogenic and Likely Pathogenic variants (PVs) detected in >220,000 individuals who underwent clinical testing with a 25-gene panel between September 2013 and March 2016. Likely somatic PVs are defined as variants with NGS read frequencies from 10% to 30%. Overall, 137 (0.06%) individuals were identified as carrying likely somatic PVs, most commonly in TP53 (73), CHEK2 (27), and ATM (20). Among this group, a second PV with a NGS read frequency consistent with a germline variant within the same gene or a different gene on the panel was detected in 21 individuals (15.3%), which is similar to the detection rate in our general testing population. Likely somatic PVs accounted for 38.8% of all PVs in TP53. In comparison, likely somatic PVs accounted for <1% of PVs in most other genes. Likely somatic PVs were more frequently identified in older individuals (p < 0.001). Additional studies are ongoing to further investigate the incidence and clinical implications of somatic variants, enabling the appropriate medical management for these patients.

Impact of Payer Constraints on Access to Genetic Testing.

BACKGROUND: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. METHODS: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. RESULTS: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. CONCLUSION: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.

BACKGROUND: As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. METHODS: A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. RESULTS: PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged <40 years, lower among women aged >59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. CONCLUSIONS: These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721-1730. © 2017 American Cancer Society.

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

Increased Identification of Candidates for High-Risk Breast Cancer Screening Through Expanded Genetic Testing.

PURPOSE: Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone. METHODS: Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history. RESULTS: In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model. CONCLUSIONS: Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.

The influence of a gene expression signature on the diagnosis and recommended treatment of melanocytic tumors by dermatopathologists.

It is well documented that histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature has been clinically validated as an adjunctive diagnostic test to differentiate benign nevi from malignant melanomas. This study aimed to quantify the impact of this test on diagnosis and treatment recommendations made by dermatopathologists.Diagnostically challenging melanocytic lesions encountered during routine dermatopathology practice were submitted for gene expression testing and received a melanoma diagnostic score (MDS). Submitting dermatopathologists completed a survey documenting pre-test diagnosis, level of diagnostic confidence, and recommendations for treatment. The survey was repeated after receiving the MDS. Changes between the pre- and post-test surveys were analyzed retrospectively.When the MDS was available as part of a comprehensive case evaluation in diagnostically challenging cases, definitive diagnoses were increased by 56.6% for cases that were initially indeterminate and changes in treatment recommendations occurred in 49.1% of cases. Treatment recommendations were changed to align with the test result in 76.6% of diagnostically challenging cases.The MDS impacts diagnosis and treatment recommendations by dermatopathologists confronted with diagnostically challenging melanocytic lesions. Increased data are needed in order to completely understand how use of the MDS will translate from dermatopathology to clinical practice.

Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma.

PURPOSE: The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. METHODS: Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer-specific mortality as the primary outcome. RESULTS: In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer-specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14-2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer-specific mortality (HR=1.77; 95% CI, 1.18-2.66; P=0.006). Five-year lung cancer-specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer-specific survival (P<0.001 and 0.015, respectively), compared with low mPS. CONCLUSION: This study validates CCP score and mPS as independent prognostic markers for lung cancer-specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.

PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. METHODS: Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. RESULTS: Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. CONCLUSION: Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.