Multigene Panel Testing Research Articles

Cost-effectiveness analysis of genotype-guided optimization of major depression treatment in Qatar.

Pharmacogenetic testing improves the efficacy and safety of antidepressant pharmacotherapy for moderate-severe major depressive disorder by identifying genetic variations that influence medication metabolism, and adjusting treatment regimens accordingly. This study aims to assess the cost-effectiveness of implementing a pharmacogenetic testing approach to guide the prescription of antidepressants. From the public hospital perspective, we developed a two-stage decision tree diagram of a short-term 6-week follow up, and a lifetime Markov model with 3-month cycles. The analysis compared the current standard of care with the alternative strategy of Pharmacogenetic-guided (multi-gene panel) testing in adult patients with moderate-severe major depressive disorder. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were locally available. The short-term incremental cost-effectiveness ratio was against treatment response without side effects and without relapse, and against treatment response with/without side effects and without relapse. The long-term incremental cost-effectiveness ratio was against the quality-adjusted life year gained and years of life saved. Adopting the pharmacogenetic-guided therapy for adult patients with moderate-severe major depressive disorder in Qatar resulted in cost savings of Qatari Riyal 2,289 (95% confidence interval, -22,654-26,340) for the health system. In the short term, the pharmacogenetic-guided testing was associated with higher response rates without side effects and without relapse (mean difference 0.10, 95% confidence interval 0.09-0.15) and higher response rates with or without side effects and without relapse (mean difference 0.05, 95% confidence interval 0.04-0.06). For long term, the pharmacogenetic-guided testing resulted in 0.13 years of life saved and 0.06 quality-adjusted life year gained, per person, along with cost savings of Qatari Riyal 46,215 (95% confidence interval-15,744-101,758). The sensitivity analyses confirmed the robustness of the model results. Implementing pharmacogenetic testing to guide antidepressant use was found to improve population health outcomes, while also significantly reducing health system costs.

Robot-Assisted Surgery and Multigene Panel Testing for Pheochromocytoma and Paraganglioma Syndrome

Robot-Assisted Surgery and Multigene Panel Testing for Pheochromocytoma and Paraganglioma Syndrome

Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres.

Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 80% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.

12490 Management Of Autoimmune Hepatitis Under Mitotane Therapy: Reintroduction Of Mitotane Under High Dose Corticosteroids For Targeted Mitotane Therapeutic Levels In A Patient With Recurrent Myxoid Adrenocortical Carcinoma

Abstract Disclosure: T. Hristova: None. D. Fenyves: None. C. Cloutier: None. M. Latour: None. Z. El-haffaf: None. P. Karakiewicz: None. H.J. Olney: None. I. Bourdeau: None. Histologically rare variants of adrenocortical carcinoma (ACC) include myxoid, oncocytic and sarcomatoid subtypes. There are about 50 reported cases of myxoid variants up to now that are described as more aggressive than classical ACC with poorer overall survival. Surgical resection offers the best chance of survival, with mitotane being the first line of treatment after surgery. Mitotane is currently the only approved adrenolytic drug for ACC. Among mitotane adverse effects, auto-immune hepatitis (AIH) is reported in monography, yet barely anything is reported in the literature about it. The precise mechanism of AIH has not been reported yet, but the mainstem therapy of AIH is corticosteroids alone or in combination with azathioprine. We report the case of a 43-year-old male who was diagnosed with non-secreting myxoid ACC subtype stage 2 (7x6x5,5 cm, ki67 18%, Weiss score 6/9). Multigene panel testing revealed a germline pathogenic variant in the ATM gene. Post adrenalectomy, mitotane was initiated within 2 months and increased to 2,5g daily within 6 weeks. 11 weeks after starting mitotane, liver enzymes were as follows: ALT 127 U/L (N: 10-39), AST 54 U/L (N: 13-39), ALP 165 U/L (N: 36-110), GGT 489 U/L (N: 9-47), while pre-mitotane levels were normal. Although mitotane was stopped, ALT increased to 255 U/L and remained high for 10 weeks after its cessation. Liver biopsy showed chronic hepatitis with moderate inflammation which was compatible with toxic hepatitis vs AIH. As kinetic liver enzyme tests increased after mitotane cessation, AIH was the retained diagnosis. Treatment with 40mg prednisone daily was then initiated. Pre-prednisone liver enzymes were ALT 202 U/L, AST 64 U/L, ALP 154 U/L, GGT 216 U/L, whereas 8 weeks later values had decreased to ALT 74 U/L, AST 20 U/L, ALP 108 U/L, GGT 84 U/L, and prednisone was lowered to 15mg daily. ACC recurred 3 months later, about one year after the initial adrenalectomy. After surgical resection, mitotane was restarted at 500mg daily with prednisone 40mg daily. As liver enzymes were within normal ranges, mitotane was slowly increased to 2.5g daily, with mitotane plasma levels of 11.3mg/L, whereas prednisone was decreased gradually to 12.5mg daily. Second ACC recurrence occurred one year later and mitotane was further increased to 3g daily under prednisone 12.5mg reaching mitotane levels up to 21.2 mg/L with surgical debulking. Further therapeutic avenues are being considered for a rapid recent ACC recurrence, such as PARP inhibitors for targeted therapy in the context of ATM gene mutation, but further considerations are required due to previous AIH. To the best of our knowledge this is the first reported case of AIH due to mitotane in a rare ACC subtype in a patient carrying a germline ATM gene mutation. We also report restart of mitotane therapy with concomitant high dose prednisone in the context of ACC recurrence that allowed to reach targeted therapeutic levels. Presentation: 6/1/2024

JS6-1 Cancer precision medicine and multi-gene panel testing (MGPT) overview

JS6-1 Cancer precision medicine and multi-gene panel testing (MGPT) overview

Multi-Gene Panel Testing for Hereditary Cancer Predisposition Among Patients Sixty-Five Years and Above Diagnosed With Breast Cancer.

The availability and affordability of germline genetic testing (GGT) has resulted in a broader utilization in daily clinical practice. However, adherence to testing guidelines is low, especially among older patients, where testing is often not offered. In this study, consecutive, newly diagnosed patients with breast cancer (BC) aged ≥ 65 years and eligible for GGT, as per the National Comprehensive Cancer Network (NCCN) guidelines (version 1, 2021), were invited to participate, from March 2021 to December 2022. Patients were offered a restricted (two- or 20-gene panel), or an expanded 84-gene panel. During the study period, 204 patients were enrolled. The mean (standard deviation (SD)) age at BC diagnosis was 70.5 (5.13) years, ranging 65 - 81 years. All patients were Arab and the majority were Jordanian. The majority (n = 188, 92.2%) had early-stage (stages I and II) disease. One hundred three (50.5%) patients were tested with a restricted two-gene (n = 13) or 20-gene (n = 90) panel, while the remaining 101 (49.5%) patients had an expanded 84-gene panel. Family history of close blood relative(s) with BC was the most common indication for testing (n = 110, 53.9%). Among the entire study cohort, 22 (10.8%) had pathogenic/likely pathogenic germline variants (PGVs) and another 97 (47.5%) had ≥ 1 variants of uncertain significance (VUS). PGV rates were significantly higher with the expanded panel (14.9%) compared to restricted testing (6.8%) (P = 0.032). Similarly, VUS rates were significantly higher with the expanded panel (64.4%) compared to the restricted panel (31.1%) (P < 0.001). The most prevalent genes with PGVs were BRCA1/2 (31.3% of all PGV-positive patients), CHEK2 (23.1%) and ATM (19.2%). GGT should not be overlooked in older BC patients, as this study demonstrates that > 10% of patients have PGVs, largely in potentially actionable genes.

Poor compliance with germline testing recommendations in colorectal cancer patients undergoing molecular residual disease testing.

Approximately 15% of colorectal cancers (CRCs) are associated with germline mutations. There is increasing adoption of DNA-based assays for molecular residual disease (MRD) and growing evidence supporting its clinical utility, particularly for CRC by oncologists in the U.S. We assessed the uptake of germline multi-gene panel testing (MGPT) for hereditary cancer in CRC patients receiving MRD analyses in community oncology settings. This retrospective study included 80 patients receiving care for CRC through community oncology practices who were referred for MRD testing at a commercial laboratory (January-March 2022). Clinical data, including test requisition forms, pathology reports, and clinical notes were reviewed. Documentation of tumor microsatellite instability and/or immunohistochemical (IHC) testing for mismatch repair (MMR) deficiency, age of CRC diagnosis, family history of cancer, and any order or recommendation for MGPT were assessed. Overall, 5/80 (6.3%) patients in the study have documented germline MGPT; 65/80 (81.3%) patients have documented MMR testing of their colorectal tumor. Among the 5 cases with abnormal MMR IHC, 2 have MGPT. Of the 33 patients meeting the 2021 National Comprehensive Cancer Network (NCCN) criteria for genetic/familial high-risk assessment, only 2 have MGPT. Our real-world data suggest that many CRC patients receiving MRD testing and meeting NCCN (v. 2021) criteria for germline MGPT may not be receiving evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing among CRC patients regardless of age at diagnosis or MMR status.

Abstract B100: Improving access to hereditary cancer genetic testing in diverse populations: Outcomes in over 33,000 patients tested by genetics and non-genetics providers in Kaiser Permanente Southern California

Abstract Kaiser Permanente Southern California is an integrated health care organization serving over 4.7 million members in 14 medical centers. KPSC members are 42% Hispanic/Latino, 28 % Non-Hispanic White, 11% Asian/Pacific Islander, 8% Black/African American, and 12% Other/Unk. To facilitate detection of hereditary cancer syndromes among patients with personal and/or family histories of breast, colorectal, ovarian, pancreas and other cancers, we offered a 48-gene hereditary cancer multigene-panel test designed to detect all the most common hereditary cancer conditions. Patients seen by genetic counselors or geneticists (Gen providers) receive pre-test genetic counseling and include those with a family history of cancer with or without personal history of cancer. Our mainstreaming program allows non-genetics (non-Gen) providers including medical and surgical oncologists, gastroenterologists, and other specialists to order the test at the point of care (based on NCCN criteria) on their patients with cancer without pre-test genetic counseling. Providers place the order in the EMR system and patients receive an email/text message with information about the test, potential results, links to educational videos and a Genetics phone number for questions. When results are ready patients receive an automatic email/text notifying them and providing a link to their test report. Those with a positive test result receive post-test genetic counseling. Patients with negative or uncertain significance (VUS) results receive a message with a link to their test report, information about their result and the option to schedule a visit with genetics. From April 2021 to May 2024, we completed 33,173 tests: 13,076 (39%) ordered by non-Gen and 20,097 (61%) by Gen providers. The results distribution was similar in both groups: pathogenic/likely pathogenic (PV/LPV): 15% for Gen orders, 12% for non-Gen; VUS: 28% Gen, 30% non-Gen, and negative: 56% Gen, 58% Non-Gen. The patients tested closely reflected the diversity of our population, except for under-representation of Hisp/Latino patients and over-representation of Non-Hisp Whites: 14,400 (42%); Hisp/Latino 9,863 (29%); Asian/PI 4,279 (13%); AA/Black 3,209 (9%); and Oth/Unk 2,415 (7%). Eliminating single MUTYH variants the top 5 genes with the highest number and percentage of PV/LPV results for each of the race/ethnicity categories were as follows: AA/Black: BRCA2=60, BRCA1=38, ATM=36, MUTYH=18; Asian/PI: BRCA2=101, ATM=40, BRCA1=37, PMS2=24; Hisp/Latino: BRCA2=250, BRCA1=171, ATM=127, CHEK2=125; CDKN2A=113; Non Hisp White: CHEK2=346; BRCA2=304; ATM=200, BRCA1=196, FH=100; Oth/Unk: BRCA2=50, BRCA1=41, CHEK2=40, PALB2=30, ATM=20. Our results represent one of the largest and most diverse patient cohorts completing hereditary cancer testing from a single institution. They indicate that mainstreaming hereditary cancer testing can improve access for patients from under-represented groups and suggest differences in the frequency of deleterious variants in different hereditary cancer genes across race/ethnic groups. Citation Format: Monica Alvarado, Trevor Hoffman, Reina Haque, Hilary Kershberg, John Goff. Improving access to hereditary cancer genetic testing in diverse populations: Outcomes in over 33,000 patients tested by genetics and non-genetics providers in Kaiser Permanente Southern California [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B100.

Prevalence and spectrum of germline pathogenic variants in cancer susceptibility genes among mexican patients with exocrine pancreatic cancer

BackgroundAlthough universal germline genetic testing is recommended for patients with exocrine pancreatic cancer (PC), access to genetic testing remains limited in low- and middle-income countries. This study aims to narrow the gap in our understanding of the spectrum of germline pathogenic and likely pathogenic variants (PVs) in cancer susceptibility genes in the Mexican population. MethodsThe landscape of PVs in cancer susceptibility genes was identified by next-generation sequencing multigene panel assays among patients with PC who were enrolled in the Clinical Cancer Genomics Community Research Network prospective registry in Mexico City. ResultsFrom August 2019 to April 2023, 137 patients underwent genetic testing. The median age at diagnosis was 60 years (range 36–85), 58.4 % were women, and 38.7 % were metastatic at diagnosis. The frequency of germline PVs was 16 % (n = 22): ATM 36.4 % (n = 8), CDKN2A/p16INK4A 27.3 % (n = 6), BRCA2 9.1 % (n = 2), PALB2 9.1 % (n = 2), CHEK2 9.1 % (n = 2), TP53 4.5 % (n = 1), and NF1 4.5 % (n = 1). Additionally, 2 carriers of monoallelic germline variants in MUTYH were identified. No significant differences were observed between carriers and non-carriers in terms of family history of pancreatic cancer. ConclusionsWe identified a significant frequency of actionable germline PVs in Mexicans with PC, wherein the majority were in a broad spectrum of genes associated with the homologous recombination DNA repair mechanism. Most pancreatic cancer associated PVs were detected in non-BRCA genes, so our findings support the recommendation of multigene panel testing for genetic cancer risk assessment of Mexican individuals with PC.

Diagnostic and clinical utility of comprehensive multigene panel testing for patients with neuropathy.

Prior to next-generation sequencing (NGS), the evaluation of a patient with neuropathy typically consisted of screening for acquired causes, followed by clinical genetic testing of PMP22, MFN2, GJB1, and MPZ in patients with a positive family history and symptom onset prior to age 50. In this study, we examined the clinical utility of NGS in a large cohort of patients analyzed in a commercial laboratory. A cohort of 6849 adult patients underwent clinician-ordered peripheral neuropathy multigene panel testing ranging from 66 to 111 genes that included NGS and intragenic deletion/duplication analysis. A molecular diagnosis was identified for 8.4% of the cohort (n = 573/6849). Variants in PMP22, MFN2, GJB1, MPZ, and TTR accounted for 73.8% of molecular diagnoses. Results had potential clinical actionability for 398 (69.5%) patients. Our results suggest that 225/573 (39.3%) of molecular diagnoses and 113/398 (28.4%) of clinical interventions would have been missed if the testing approach had been restricted to older guidelines. Our results highlight the need for expanded genetic testing guidelines that account for the increased number of genes associated with hereditary neuropathy, address the overlap of acquired and hereditary neuropathy, and provide broader access to genetic diagnosis for patients.

Phenotypes of carriers of two mutated alleles in major cancer susceptibility genes.

While cancer phenotypes in carriers of a single mutant allele in most major cancer susceptibility genes are well-established, there is a paucity of data on the phenotype of carriers of two pathogenic variants-double heterozygotes (DH) or homozygous carriers. Here, we describe the phenotype of carriers of homozygous and DH pathogenic sequence variants (PSVs) in major cancer susceptibility genes. Individuals referred for multigene panel testing at Blueprint Genetics laboratory were included. Ethically approved comparison of cancer type and age at diagnosis between DH, homozygous, and single PSV carriers was performed per gene. Of 6,685 eligible participants, 928 (13.9%) were single heterozygous PSV carriers, 6 (0.09%) were homozygous PSV carriers, and 17 (0.25%) were DH PSV carriers. Mean age at diagnosis of any cancer among single PSV age was 46.8 ± 14.9 years and among DH PSV carriers 37.6 ± 13.0 years (P < 0.0001). Notably, age at diagnosis for breast cancer among single BRCA1 PSV carriers (n = 59) was 43.8 ± 8.7 years (p = 0.7606), among single BRCA2 PSV carriers (n = 52)-47.9 ± 13.0 years (p = 0.2274) compared with 42.3 ± 13.0 years among DH PSV carriers (n = 10- 9 of whom were carriers of either BRCA1 or BRCA2). DH for PSV in two cancer susceptibility genes is a rare event, and the mean age at cancer diagnosis is younger in DH PSV carriers compared with single PSV carriers.

Hereditary breast cancer next-generation sequencing panel evaluation in the south region of Brazil: A novel BRCA2 candidate pathogenic variant is reported.

In this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.

Integration and Outcomes of Universal, Multigene Panel Testing for Newly Diagnosed Breast Cancer Patients at a Community Healthcare System

Integration and Outcomes of Universal, Multigene Panel Testing for Newly Diagnosed Breast Cancer Patients at a Community Healthcare System

Multi-gene panel analysis in BRCA1/2-negative patients suspected of hereditary breast and ovarian cancer syndrome: Real-world data from a single institution.

Although BRCA1/2 is most frequently associated with hereditary breast and ovarian cancer (HBOC), many other related genes have been implicated. Therefore, we investigated the prevalence of non-BRCA1/2 genes associated with hereditary cancer predisposition in BRCA1/2-negative patients from the Department of Genetic Medicine and Services with breast and ovarian cancer using a multi-gene panel (MGP) analysis. We conducted a retrospective MGP analysis (National Cancer Center Onco-Panel for Familial Cancer; NOP_FC) in BRCA1/2-negative patients with breast, ovarian, and overlapping breast/ovarian cancers who visited our genetic counseling between April 2004 and October 2022. NOP_FC was performed in 128 of the 390 BRCA test-negative cases (117 breast cancer, 9 ovarian cancer, and 2 overlapping breast/ovarian cancer cases). Among the BRCA1/2-negative patients, nine (7.7%) with breast cancer and one (11%) with ovarian cancer had pathogenic variants (PVs) in non-BRCA1/2 genes associated with breast and ovarian cancers, respectively. Five patients had PVs in RAD51D, two in PALB2, one in BARD1, one in ATM, and one in RAD51C. Additional MGP testing of germline genes associated with hereditary cancer predisposition syndrome in BRCA1/2-negative breast and ovarian cancer patients revealed PVs in non-BRCA1/2 breast cancer- and ovarian cancer-related genes in 7.7% of breast cancer and 11% of ovarian cancer. Therefore, additional testing may provide useful information for subsequent risk-reducing surgery and surveillance in BRCA1/2-negative patients.

Cardiometabolic Risk Markers in Children With Obesity and Variants in MC4R Pathway-related Genes.

Variants in melanocortin 4 receptor (MC4R) pathway-related genes have been associated with obesity. The association of these variants with cardiometabolic parameters are not fully known. We compared the severity of obesity and cardiometabolic risk markers in children with MC4R pathway-related clinically reported genetic variants relative to children without these variants. A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the MC4R pathway, and the remaining 65 patients did not have reported MC4R pathway-related variants. Among the MC4R-related variants, PCSK1 risk alleles were most common, reported in 15 children (14%). The maximum body mass index percent of the 95th percentile was not different between groups (P = .116). Low-density lipoprotein cholesterol (LDL-C) was not different between groups (P = .132). However, subgroup analysis demonstrated higher LDL cholesterol in children with the PCSK1 c.661A>G risk allele relative to those with MC4R-related variant of uncertain significance (P = .047), negative genetic testing (P = .012), and those with non-MC4R related variants (P = .048). The blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, alanine transaminase, and high-density lipoprotein cholesterol were not different between groups. Variants in the MC4R pathway-related genes were not associated with severity of obesity and cardiometabolic risk markers except for the c.661A>G PCSK1 risk allele, which was associated with higher LDL-C levels.

Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort

PurposeTo provide a genotype and phenotype characterization of the BEST1 mutation in Chinese patients with autosomal recessive bestrophinopathy (ARB) through multimodal imaging and next-generation sequencing (NGS).MethodsSeventeen patients from 17 unrelated families of Chinese origin with ARB were included in a retrospective cohort study. Phenotypic characteristics, including anterior segment features, were assessed by multimodal imaging. Multigene panel testing, involving 586 ophthalmic disease-associated genes, and Sanger sequencing were performed to identify disease-causing variants.ResultsAmong 17 ARB patients, the mean follow-up was 15.65 months and average onset age was 30.53 years (range: 9–68). Best corrected visual acuity ranged from light perception to 0.8. EOG recordings showed a typically decreased Arden ratio in 12 patients, and a normal or slightly decreased Arden ratio in two patients. Anterior features included shallow anterior chambers (16/17), ciliary pronation (16/17), iris bombe (13/17), iridoschisis (2/17), iris plateau (1/17), narrow angles (16/17) and reduced axial lengths (16/17). Sixteen patients had multiple bilateral small, round, yellow vitelliform deposits distributed throughout the posterior pole, surrounding the optic disc. Initial diagnoses included angle-closure glaucoma (four patients), Best disease (three patients), and central serous chorioretinopathy secondary to choroidal neovascularization (CNV) (one patient), with the remainder diagnosed with ARB. Fourteen patients underwent preventive laser peripheral iridotomy, four of whom also received combined trabeculectomy and iridotomy in both eyes for uncontrolled intraocular pressure. One patient received intravitreal conbercept for CNV. Overall, 15 distinct disease-causing variants of BEST1 were identified, with 14 (82.35%) patients having missense mutations. Common mutations included p. Arg255-256 and p. Ala195Val (both 23.68%), with the most frequent sites in exons 7 and 5.ConclusionsThis study provides a comprehensive characterization of anterior segment and genetic features in ARB, with a wide array of morphological abnormalities. Findings are relevant for refining clinical practices and genetic counseling and advancing pathogenesis research.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.

Real-world genetic testing outcomes of pan-cancer testing for mismatch repair deficiency.

In 2017, the Food and Drug Administration approved pembrolizumab for treatment of any mismatch repair-deficient (dMMR) tumor making MMR immunohistochemistry (IHC) testing beneficial for all tumor types. For the first time, MMR IHC was not performed exclusively to screen for Lynch syndrome (LS). In this study, all MMR IHC reports issued between 2017 and 2021 at an academic hospital were reviewed and completion of genetic testing was determined through chart review. Colorectal cancers (CRCs), endometrial cancers (ECs), and noncancerous lesions were excluded. Between 2017 and 2021, MMR IHC was completed in 1939 patients with a malignancy other than CRC or EC. Absent or weak staining for at least one MMR protein was detected in 115 (5.9%) patients and 59 (51%) of those completed germline genetic testing. Overall, the identification rate of LS in this cohort was 0.72%, which is similar to the rate in our previously reported CRC and EC universal screening cohort. A diagnosis of LS was most commonly made in patients with dMMR brain (18.75%) and small intestinal cancers (10.20%). Five additional patients were found to carry a pathogenic variant in a non-LS gene. Pan-cancer MMR testing for pembrolizumab consideration can identify LS cases at a rate similar to universal CRC and EC screening programs. A persistent challenge is subsequent uptake of genetic testing. MMR testing should be prioritized in brain and small intestinal tumors, and multigene panel testing is recommended in patients with dMMR, as unexpected pathogenic variants in non-LS genes were found as frequently as LS gene variants.

TP53 p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil.

Despite the high prevalence of TP53 pathogenic variants (PV) carriers in the South and Southeast regions of Brazil, germline genetic testing for hereditary breast cancer (HBC) is not available in the Brazilian public health system, and the prevalence of Li-Fraumeni syndrome (LFS) is not well established in other regions of Brazil. We assessed the occurrence of TP53 p.R337H carriers among women treated for breast cancer (BC) between January 2021 and January 2022 at public hospitals of Brasilia, DF, Brazil. A total of 180 patients who met at least one of the NCCN criteria for HBC underwent germline testing; 44.4% performed out-of-pocket germline multigene panel testing, and 55.6% were tested for the p.R337H variant by allelic discrimination PCR. The median age at BC diagnosis was 43.5 years, 93% had invasive ductal carcinoma, 50% had estrogen receptor-positive/HER2 negative tumors, and 41% and 11% were diagnosed respectively at stage III and IV. Two patients (1.11%) harbored the p.R337H variant, and cascade family testing identified 20 additional carriers. The TP53 p.R337H detection rate was lower than that reported in other studies from south/southeast Brazil. Nonetheless, identifying TP53 PV carriers through genetic testing in the Brazilian public health system could guide cancer treatment and prevention.

Predictive modeling for the germline pathogenic variant of the APC gene in patients with adenomatous polyposis: proposing a new APC score.

The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. Ninety (55.6%) patients had GPV of the APC gene. According to a multivariate logistic regression analysis, age < 40years, polyps ≥ 100, fundic gland polyposis, and a family history of colorectal polyposis were found to be independent predictors of the GPV of APC and were used to establish a formula for predicting the GPV of APC using the four predictors. The prediction model had an area under the curve of 0.91 (0.86-0.96) according to a receiver operating characteristic analysis. The model for predicting the GPV of APC will help patients with adenomatous polyposis and physicians make decisions about genetic testing.