scholarly journals Pathogenic Variants in Less Familiar Cancer Susceptibility Genes: What Happens After Genetic Testing?

2018 ◽  
pp. 1-10
Author(s):  
Evan T. Hall ◽  
Divya Parikh ◽  
Jennifer L. Caswell-Jin ◽  
Tanya Gupta ◽  
Meredith A. Mills ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Risk Reducing

Purpose As genetic testing expands, patients are increasingly found to carry pathogenic variants in cancer susceptibility genes that are less familiar to most clinicians, specifically genes other than those causing hereditary breast ovarian cancer syndrome ( BRCA1 and BRCA2) and Lynch syndrome. Little is known about the subsequent behaviors of such patients in terms of managing cancer risks and informing relatives. Methods All adult patients who were counseled and tested at the Stanford Cancer Genetics Clinic from January 2013 to July 2015 and had a pathogenic variant in a non- BRCA1/2, non–Lynch syndrome gene were invited to participate in a telephone interview about adherence to risk-reducing recommendations, genetic testing by relatives, and new cancer incidence. Results Fifty-seven (40%) of 142 eligible patients were successfully contacted, and all 57 patients participated; median follow-up was 677 days (range, 247 to 1,401 days). Most patients (82%; 95% CI, 70% to 90%) recalled that a risk-reducing intervention (screening, medication, or surgery) was recommended, and most patients (85%; 95% CI, 72% to 93%) adhered to the recommendation. Nearly all patients (91%; 95% CI, 81% to 97%) shared results with relatives, and most patients (78%; 95% CI, 64% to 88%) reported that a relative was subsequently tested. During the follow-up period, 9% of patients (95% CI, 3% to 19%) developed second cancers, and in 14% of patients (95% CI, 7% to 26%), a first-degree relative developed cancer, some of which were detected by recommended screening. Conclusion Patients with a pathogenic variant in a less familiar cancer susceptibility gene report high adherence to risk-reducing interventions. Furthermore, in the 57 carriers and subsequently tested relatives with two years of follow-up, a total of three cancers (one in a proband and two in relatives) were detected through interventions recommended on the basis of the pathogenic variant. These results suggest a potential benefit of genetic counseling and testing for pathogenic variants in less familiar genes.

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 560-560 ◽  
Author(s):  
Allison W. Kurian ◽  
Kevin C. Ward ◽  
Paul Abrahamse ◽  
Ann S Hamilton ◽  
Dennis Deapen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

560 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening

2020 ◽  
Vol 38 (13) ◽  
pp. 1398-1408 ◽  
Author(s):  
Kenneth Offit ◽  
Kaitlyn A. Tkachuk ◽  
Zsofia K. Stadler ◽  
Michael F. Walsh ◽  
Hector Diaz-Zabala ◽  
...  
Keyword(s):  
United States ◽  
Genetic Testing ◽  
Family Size ◽  
Cancer Susceptibility ◽  
The United States ◽  
Susceptibility Genes ◽  
Cancer Genetic ◽  
Patients With Cancer ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

PURPOSE Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information. METHODS Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size. RESULTS The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations. CONCLUSION Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

Adherence to breast cancer treatment guidelines according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 34-34
Author(s):  
Steven J. Katz ◽  
Monica Morrow ◽  
Allison W. Kurian
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

34 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N=77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy of stage <IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score <30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N=1,283). Compared to women with negative results, those with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation as initial treatment. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer

JAMA ◽  
2020 ◽  
Vol 323 (10) ◽  
pp. 995 ◽  
Author(s):  
Allison W. Kurian ◽  
Ryan Bernhisel ◽  
Katie Larson ◽  
Jennifer L. Caswell-Jin ◽  
Aladdin H. Shadyab ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Postmenopausal Breast Cancer ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1547-1547
Author(s):  
Zachary Phillip Schwartz ◽  
Mae Zakhour ◽  
Andrew John Li ◽  
Christine S. Walsh ◽  
Bj Rimel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Susceptibility ◽  
Brca Mutation ◽  
Susceptibility Genes ◽  
Brca Mutations ◽  
Cancer Susceptibility Genes ◽  
Mutation Carriers ◽  
Brca Mutation Carriers ◽  
History Of ◽  
Risk Reducing

1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]

Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The genetic education, risk assessment and testing (GENERATE) study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4162-TPS4162
Author(s):  
Matthew B. Yurgelun ◽  
C. Sloane Furniss ◽  
Barbara Kenner ◽  
Alison Klein ◽  
Catherine C. Lafferty ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Cancer Worry ◽  
Genetic Education ◽  
Degree Relative ◽  
Cascade Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Testing

TPS4162 Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same pathogenic variant (cascade testing), thereby providing the opportunity for early detection and cancer interception of PDAC and other associated malignancies. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC susceptibility. Methods: 1000 individuals (from approximately 200 families) with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.generatestudy.org) and randomized between two different methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. Participants in both arms will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include participant self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment will begin February, 2019. Clinical trial information: NCT03762590.

scholarly journals A Case-Based Approach to Understanding Complex Genetic Information in an Evolving Landscape

2021 ◽  
pp. 1-11
Author(s):  
Courtney D. DiNardo ◽  
Larissa A. Korde ◽  
Matthew B. Yurgelun
Keyword(s):  
Genetic Testing ◽  
Genetic Information ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Somatic Mosaicism ◽  
Inherited Cancer ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Technological Advances ◽  
Case Based

The rapid integration of highly sensitive next-generation sequencing technologies into clinical oncology care has led to unparalleled progress, and yet these technological advances have also made genetic information considerably more complex. For instance, accurate interpretation of genetic testing for germline/inherited cancer predisposition syndromes and somatic/acquired pathogenic variants now requires a more nuanced understanding of the presence and incidence of clonal hematopoiesis and circulating tumor cells, with careful evaluation of pathogenic variants occurring at low variant allele frequency required. The interplay between somatic and germline pathogenic variants and awareness of distinct genotype-phenotype manifestations in various inherited cancer syndromes are now increasingly appreciated and can impact patient management. Through a case-based approach, we focus on three areas of particular relevance to the treating clinician oncologist: (1) understanding clonal hematopoiesis and somatic mosaicism, which can be detected on germline sequencing and lead to considerable confusion in clinical interpretation; (2) implications of the detection of a potentially germline pathogenic variant in a high-penetrance cancer susceptibility gene during routine tumor testing; and (3) a review of gene-specific risks and surveillance recommendations in Lynch syndrome. A discussion on the availability and difficulties often associated with direct-to-consumer genetic testing is also provided.

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