Testing For Hereditary Cancer Predisposition Research Articles

Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer

Germline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited. To assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population. This cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. The main outcomes were germline sequence variation prevalence and spectrum in patients with AC. Among the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T>A, p.I1307K], 2 with CHEK2 [c.470T>C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G>A, p.R175H]). In this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.

Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer

DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.

GeneHome - a Novel Model to Deliver Care to Individuals with Genetic Predisposition to Cancer.

Genetic testing for hereditary cancer predisposition is more widely available, resulting in more patients being identified as carriers of pathogenic variants (PV) of cancer susceptibility genes. PV carriers may be at high risk for multiple cancers of different organ systems. Traditional high-risk cancer screening is often organ specific and conducted separately by specialists. However, with many genes associated with 3 or more types of cancer risks, coordination of such cancer screening can be overwhelming for patients and providers. At Moffitt Cancer Center (MCC), GeneHome clinic functions as a “home” to conduct and coordinate prevention, screening, counseling, and education for individuals carrying germline genetic PVs across the entire spectrum of cancer genes. The screening includes, but is not limited to, history review, physical examination, image studies, blood tests, urine tests, and endoscopy. GeneHome is a novel model for genetic high-risk cancer surveillance and has grown in 4 years since establishment. We sought to study various characteristics of the patient population it serves, common themes in referral patterns and evolution of the clinic since its inception. A total of 821 patients were seen over 42 months, encompassing PV carriers of 46 genes. Patients were 84.9% female and 13.3% male. Most PVs were of BRCA1 and BRCA2. Most patients had private insurance, and most were from Florida. Annual increase in patient visits was over 74.7% over the last year. Overall, GeneHome has been well accepted by providers and patients and is a valuable service for patients with a genetic predisposition to cancer.

Errors in Genetic Testing: The Fourth Case Series

In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.

EMR documentation of genetics evaluations in patients with ovarian cancer.

e13156 Background: Genetic testing for hereditary cancer predisposition has become increasingly complex yet impactful. Provider knowledge of test results influences risk management, implications for family members, and therapeutics. Currently, it’s unknown if genetic test (GT) results are appropriately recorded and accessible within the electronic medical record (EMR). Methods: We conducted a single-institution retrospective chart review to examine clinical diagnoses, family history of cancer, genetics referrals, and genetics services received at University of Pennsylvania’s Cancer Risk Evaluation Program (CREP) or elsewhere. The study cohort included new and prevalent cases of ovarian cancer (OC) seen by either a gynecologic or medical oncologist at the University of Pennsylvania in 2016. Analyses were conducted using SAS 9.4. Results: 667 women (83% white, 9% black, 4% Asian; mean age 61) with OC were included. 58% had a documented family history of breast, ovarian, prostate or pancreas cancer. 48% had documentation of referral to genetic testing and an additional 26% had documentation of testing outside of CREP. 26% had no documentation of referral or testing. Of those referred to CREP, 75% had genetic testing: in total 62% of the cohort had documented testing. 94% of those tested had a result documented in a provider note, and 64% had a scanned testing report uploaded into the EMR, including 74.3% of those tested through CREP and 25.7% of those tested outside. Among the 118 pathogenic mutations, 70% were documented on the EMR “problem list.” Conclusions: In this study, most, though not all, OC patients had documentation of a GT referral or testing in the EMR. Although GT results were routinely included in progress notes, these reports were less commonly scanned into the EMR (particularly for those tested outside Penn) or included in the EMR “problem list” which is both searchable and immediately visible. Capturing genetic data in a uniform and easily accessible manner within the EMR is necessary to maximize clinical utility of this information and should be a focus for EMR module development.

Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing

Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM, commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2 and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p<0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p<0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results.

The effects of genomic germline variant reclassification on clinical cancer care.

The last two decades have provided an astounding amount of novel information about the human genome. Translating germline genomic data into clinically actionable findings is reliant on the annotation and laboratory classification of specific variants. Variant classification helps providers and patients determine if genomic findings can inform clinical management. In germline hereditary cancer predisposition testing, variants of uncertain significance (VUS) are routinely misunderstood. By definition, they cannot be classified by the testing laboratory as either problematic mutations or benign variants. Many VUS undergo category reclassifications over time (from months to years after initial classification) as more information is known about normal human genomic diversity, especially among underrepresented minority populations. When VUS are reclassified, it has been shown that they are often downgraded. Likewise, some variants originally thought to be actionable mutations are downgraded to VUS or benign variants. Rarely but importantly, VUS may be reclassified in a manner that increases their initial clinical significance. Here, we discuss the insights gained from the study of variant reclassification. We provide a case series to highlight the potential impact that variant reclassifications can have on individual and family cancer management, risk counseling, and screening.

Abstract 3406: Hereditary risks of male breast cancer in a multi-gene panel testing cohort

Abstract While the population-based risk for breast cancer in males remains relatively low (1:1000), inherited predisposition can significantly raise this to as high as 10%, in men who carry a mutation in the BRCA2 gene. Lifetime breast cancer risks of 1-2% have also been reported in men who carry a mutation in BRCA1. These risks, as well as elevated risks of prostate, pancreatic, and melanoma cancers, are important to discuss in families diagnosed with Hereditary Breast and Ovarian Cancer Syndrome, which is often viewed as being clinically relevant only to the women in an affected family. However, beyond the BRCA1/2 genes, limited data is available on hereditary predisposition to male breast cancer. We analyzed clinical histories and molecular results from multi-gene panel testing for hereditary cancer predisposition in a cohort of 715 men affected by breast cancer. A total of 708 male breast cancer patients were eligible for inclusion in the final analysis. Molecular testing included analysis of 5 to 59 genes for DNA coding sequence and copy number variants by next-generation sequencing and microarray. Genetic variants identified were classified according to a 5-tier system using previously validated algorithms1,2. Only those variants classified as pathogenic or likely pathogenic were included in the analyses as positive for a mutation. Overall, a mutation was detected in 18% of these men. Four subjects carried a mutation in two different breast cancer predisposition genes. BRCA2 and CHEK2 were the most frequently mutated genes. The risk of breast cancer was significantly elevated compared to public controls in individuals with a mutation in BRCA2 (odds ratio (OR)=13.9; p=1.92x10-16), CHEK2 (OR=3.8; p=6.24x10-24) and PALB2 (OR=6.6, p=0.01). Average age was similar amongst men with (63.5±2.7 years) and without (62.3±1.2 years) mutations, as were clinical and family histories of additional cancers. The high overall diagnostic yield suggests the utility of testing all male breast cancer patient regardless of age or family history by multigene panel testing, and provides data to support risk-based counseling and medical recommendations for screening and/or prevention in male mutation carriers. 1. 1. LaDuca et al. Genet Med. 2014 Nov;16(11):830-7 2. 2. Richards et al. Genet Med. 2015 May;17(5):405-24 Citation Format: Elizabeth C. Chao, Mary Pritzlaff, Summerour Pia, Rachel McFarland, Shuwei Li, Jill Dolinsky, David Goldgar, Hermela Shimelis, Fergus Couch, LaDuca Holly. Hereditary risks of male breast cancer in a multi-gene panel testing cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3406. doi:10.1158/1538-7445.AM2017-3406

Are we still adjusting to multigene panel testing? An NCI-designated cancer center's 2-year experience.

1585 Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p &lt; 0.001), and a smaller proportion of C tests (59% v. 74%, p &lt; 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.

Abstract P3-08-02: Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients

Abstract Background Among women with an elevated risk of hereditary breast and ovarian cancer who previously tested negative for pathogenic mutations in BRCA1 and BRCA2, a subset remain at increased risk of having hereditary breast, ovarian or other cancers, and should be offered multi-gene panel testing. We tested three groups of women who were enrolled in the UCSF Cancer Genetics and Prevention Program: (i) 97 women with a personal history of bilateral breast cancer, (ii) 104 women with a personal history of breast cancer and a first-degree or second-degree relative with ovarian cancer, and (iii) 99 women with a personal history of ovarian, fallopian tube, or primary peritoneal cancer. All women previously tested negative for pathogenic BRCA1 and BRCA2 mutations by either limited or comprehensive testing. Methods We performed comprehensive next-generation sequencing using a panel of 19 genes developed by Color Genomics (a CLIA-certified laboratory) covering ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Results Across the groups tested, 9% had pathogenic mutations in one or more of the genes analyzed (8% in genes other than BRCA1 and BRCA2). Among these women, Ashkenazi Jewish and Hispanic women had elevated mutation rates compared to those of other ethnicities. In addition, we identified two women with pathogenic mutations in two cancer susceptibility genes, which has significant implications for family testing. These results demonstrate the importance of genetic testing of genes other than BRCA1 and BRCA2. Conclusions Among women with an elevated risk of hereditary breast and ovarian cancer who have previously tested negative for BRCA1 and BRCA2 mutations, we propose that women with characteristics of any of the three groups above be considered for subsequent multi-gene panel testing. Additionally, ethnicity and the possibility of multiple mutations may be indications for additional testing in these women and in family members of carriers. Citation Format: Crawford BB, Adams SB, Sittler T, Van den Akker J, Chan SB, Leitner O, Ryan LN, Gil E, Van 't Veer LJ. Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-02.

The Advantages and Challenges of Testing Children for Heritable Predisposition to Cancer.

The increased application of germline genetic testing is expanding our understanding of the risk factors associated with childhood cancer development, and, in some cases, such testing is also informing clinical management. Nonetheless, the incorporation of genetic testing into the pediatric oncology setting is complex and associated with many ethical and practical challenges. The decision as to whether to pursue clinical genetic testing for hereditary cancer predisposition for children should always be guided by the best interest of the child. Despite this fundamental ethical principle, patients, parents, and health care providers may differ in their opinions. Clinical genetic testing to detect the presence of predisposition syndromes associated with childhood-onset cancers, particularly those for which surveillance and preventive measures have proven to enhance outcome, is currently well accepted. On the other hand, clinical genetic testing of children for syndromes associated with adult-onset cancers has raised many concerns about the potential for psychological harm and disrespect of patient autonomy. As a consequence, such testing is not encouraged. The challenges surrounding germline genetic testing are further complicated when testing is done in the research setting and/or when it involves whole-exome or whole-genome sequencing approaches, which can uncover genetic variants that may or may not be associated with the disease under study. Accordingly, there is great debate around these processes and the most appropriate approaches regarding the return of test results. Future research is needed to enhance knowledge about how best to incorporate genomic information into clinical practice.

Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients

Purpose:The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing.Methods:Panels included comprehensive analysis of 14–22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met.Results:Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria.Conclusion:Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.