scholarly journals Germline testing data validate inferences of mutational status for variants detected from tumor-only sequencing

2021 ◽  
Author(s):  
Nahed Jalloul ◽  
Israel Gomy ◽  
Samantha Stokes ◽  
Alexander Gusev ◽  
Bruce E. Johnson ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Sequencing Data ◽  
Germline Variants ◽  
Information Theoretic ◽  
Cancer Susceptibility Genes ◽  
Mutational Status ◽  
Testing Data ◽  
Uncertain Significance ◽  
Somatic Status ◽  
Germline Testing

Structured AbstractBackgroundPathogenic germline variants (PGV) in cancer susceptibility genes are usually identified in cancer patients through germline testing of DNA from blood or saliva: their detection can impact patient treatment options and potential risk reduction strategies for relatives. PGV can also be identified, in tumor sequencing assays, often performed without matched normal specimens. It is then critical to determine whether detected variants are somatic or germline. Here, we evaluate the clinical utility of computational inference of mutational status in tumor-only sequencing compared to germline testing results.Patients and MethodsTumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline-versus-somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity (LOH) was also determined. The predicted mutational models were compared to clinical germline testing results. Statistical measures were computed to evaluate performance.ResultsTumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. Our analysis imputed germline-versus-somatic status for >75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with LOH in the tumor specimens (72%) compared to variants of uncertain significance (58%).ConclusionsTumor-only sequencing provides sufficient power to distinguish germline and somatic variants and infer LOH. Although accurate detection of PGV from tumor-only data is possible, analyzing sequencing data in the context of specimens’ tumor cell content allows systematic exclusion of somatic variants, and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Our approach, implemented in a user-friendly bioinformatics application, facilities objective analysis of tumor-only data in clinical settings.HighlightsMost pathogenic germline variants in cancer predisposition genes can be identified by analyzing tumor-only sequencing data.Information-theoretic gene-independent analysis of common sequencing data accurately infers germline vs. somatic status.A reasonable statistical balance can be established between sensitivity and specificity demonstrating clinical utility.Pathogenic germline variants are more often detected with loss of heterozygosity vs. germline variants of uncertain significance.

scholarly journals Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing

2021 ◽  
pp. 1749-1757
Author(s):  
Nahed Jalloul ◽  
Israel Gomy ◽  
Samantha Stokes ◽  
Alexander Gusev ◽  
Bruce E. Johnson ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Sequencing Data ◽  
Cancer Susceptibility Genes ◽  
Statistical Measures ◽  
Mutational Status ◽  
Testing Data ◽  
Somatic Status ◽  
Germline Testing

PURPOSE Pathogenic germline variants (PGVs) in cancer susceptibility genes are usually identified through germline testing of DNA from blood or saliva: their detection can affect treatment options and potential risk-reduction strategies for patient relatives. PGV can also be identified in tumor sequencing assays, which, when performed without patient-matched normal specimens, render determination of variants' germline or somatic origin critical. METHODS Tumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline versus somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity was also determined. Predicted mutational models were compared with clinical germline testing results. Statistical measures were computed to evaluate performance. RESULTS Tumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. We imputed germline versus somatic status for > 75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with loss of heterozygosity in the tumor specimens (72%) compared with variants of uncertain significance (58%). CONCLUSION Analyzing tumor-only data in the context of specimens' tumor cell content allows precise, systematic exclusion of somatic variants and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Although technical or systematic errors in measuring variant allele frequency could result in incorrect inference, misestimation of specimen purity could result in inferring somatic variants as germline in somatically mutated tumor suppressor genes. A user-friendly bioinformatics application facilitates objective analysis of tumor-only data in clinical settings.

Confirmation of germline variants identified by tumor testing: A population-based study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13021-e13021
Author(s):  
Alexandra Pender ◽  
Aly Karsan ◽  
Stephen Yip ◽  
Ian Bosdet ◽  
Sean Young ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Driver Mutations ◽  
Low Grade ◽  
Germline Variants ◽  
Referral Rates ◽  
Therapeutic Implications ◽  
Cancer Susceptibility Genes ◽  
Germline Testing

e13021 Background: Multi-gene panel tumour testing (TT) has been available in British Columbia since mid-2016 for metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), melanoma (MEL), low-grade glioma (LGG), and gastro-intestinal stromal tumours (GIST). TT can detect somatic driver mutations and potential pathogenic germline variants (pPGVs) associated with hereditary cancer susceptibility. We reviewed the frequency of pPGVs identified by TT and examined referral rates to the Hereditary Cancer Program (HCP) for confirmatory germline testing (GT) and therapeutic implications of PGV findings. Methods: All patients (pts) undergoing TT testing from October 1, 2016 to December 31, 2018 were identified. Diagnosis, age, gender, family history and treatment data were obtained. TT was performed by next-generation sequencing for all/selected regions of the following genes: AKT1, ALK, BRAF, BRCA1, BRCA2, CCND1, CCND3, CIC, EGFR, ERBB2, ERBB3, FUBP1, HRAS, IDH1, IDH2, KIT, KRAS, MAP2K1, MET, NRAS, PDGFRA, PIK3CA, PTEN, ROS1, SDHA, SDHB, SDHC, SDHD. Results: Among 2937 TTs, pPGVs were identified in 83 pts (2.8%) [Table 1]. 50 pts (57%) were referred to HCP, 41 had germline testing, and 14 PGV were confirmed. PGVs were most commonly identified in BRCA1/2 and SDHA and these findings did not influence oncologic treatments. Conclusions: TT detected pPGVs in 2.8% of unselected pts with metastatic cancers. Among 41 pts undergoing germline testing, 34% who would not have otherwise met testing criteria, had a confirmed PGV. Referral rates were low due to lack of patient and clinician awareness and poor health status. Although PGV findings did not directly impact treatment, TT identified 14 new families with hereditary cancer who can benefit from early detection and screening. Future directions include expansion of TT to include additional hereditary cancer susceptibility genes and development of digital tools for pts and clinicians. [Table: see text]

Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 418-418
Author(s):  
Hong Truong ◽  
Rania Sheikh ◽  
Aliya Khurram ◽  
Yelena Kemel ◽  
Andrew Thomas Lenis ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Stage At Diagnosis ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
High Penetrance ◽  
Germline Testing

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.

Evaluation of germline genetic testing criteria in early-onset kidney cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 296-296
Author(s):  
Hong Truong ◽  
Rania Sheikh ◽  
Ritesh Kotecha ◽  
Yelena Kemel ◽  
Aliya Khurram ◽  
...  
Keyword(s):  
Risk Factors ◽  
Family History ◽  
Early Onset ◽  
Clear Cell ◽  
Cancer Susceptibility ◽  
Germline Variants ◽  
Panel Testing ◽  
Cancer Susceptibility Genes ◽  
History Of ◽  
Germline Testing

296 Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels

2019 ◽  
pp. 1-11
Author(s):  
Zade Akras ◽  
Brandon Bungo ◽  
Brandie H. Leach ◽  
Jessica Marquard ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Cancer Predisposition ◽  
Comprehensive Overview ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
Germline Genes ◽  
Number Of Genes ◽  
Predisposition Genes ◽  
Hereditary Cancer Predisposition

PURPOSE It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter prospective universal genetic testing study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4118-4118
Author(s):  
Pedro Luiz Serrano Uson Junior ◽  
Douglas Riegert-Johnson ◽  
Lisa A. Boardman ◽  
Mitesh J. Borad ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Outcomes ◽  
Cancer Susceptibility ◽  
Familial Cancer ◽  
Family Counseling ◽  
Disease Stage ◽  
Germline Variants ◽  
Sequencing Platform ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

scholarly journals Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma

JAMA Oncology ◽  
2020 ◽  
Vol 6 (5) ◽  
pp. 724 ◽  
Author(s):  
Lisa Mirabello ◽  
Bin Zhu ◽  
Roelof Koster ◽  
Eric Karlins ◽  
Michael Dean ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Germline Variants ◽  
Cancer Susceptibility Genes

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.

Characterization of mutations in HRR genes, TMB, and PD-L1 expression in Chinese patients with ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18048-e18048
Author(s):  
Hong Zheng ◽  
Min Gao ◽  
Weijiao Gao ◽  
Nan Zhang ◽  
Hongguo Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Detection Rate ◽  
Cancer Susceptibility ◽  
Disease Recurrence ◽  
Chinese Patients ◽  
Coding Region ◽  
Tissue Samples ◽  
Detection Rates ◽  
Germline Variants ◽  
Cancer Susceptibility Genes

e18048 Background: A great number of clinical studies have confirmed the promising efficacy of ICIs and PARPi in multiple solid tumors. Here we aim to investigate the biomarkers related to these emerging therapies, including mutations in DNA homologous recombination repair (HRR) genes, tumor mutation burden (TMB) and PD-L1 expression in Chinese patients (pts) with ovarian cancer. Methods: A total of 209 pts with ovarian cancer were enrolled. Matched tumor-normal NGS of 1021 cancer-related genes was performed in 98 pts (T: 71 pts, T+B: 25 pts, B: 2 pts). Germline variants in ovarian cancer susceptibility genes were analyzed in 209 pts. PD-L1 expression was assessed by immunohistochemistry (Dako 22C3). Pts with TPS≥50 were considered as high expression and pts with 1≤TPS<50 was considered as expression. Tissue TMB was calculated as the number of somatic non-synonymous SNVs and Indels per Mb in the coding region (with VAF ≥0.03). The threshold of TMB-high was 5.76 muts/MB. Results: Germline pathogenetic or likely pathogenetic variants were identified in 28.7% of pts ( BRCA1 15.3%, BRCA2 7.7%, RAD51D 2.0%, PALB2 1.0%, and 0.7% for CHEK2, MSH2, RAD51C and MSH6). Germline variants in HRR genes was identified in 27.3% of pts. The mutation detection rates in 96 tissue samples from surgery or biopsy and 25 ctDNA samples collected at disease recurrence were 100% and 96%, respectively. An average of 34.6% of tissue-derived mutations can be identified in ctDNA, and 55.2% of tissue-derived actionable mutations were observed in ctDNA. Besides, there were 83 private mutations, including PPMID (5), ARID2 (3), CHEK2 (3), PIK3CA (3) and ARID1B (2). Mutations in HRR genes were found in 36.5% (35/96) of tissue samples, and 12 pts harbored more than one HRR mutations. The detection rate of HRR mutations in ctDNA was 40% (10/25), and cases harbored more than one HRR mutations. The status of TMB and PD-L1 was analyzed in 30 pts. Two pts were evaluated as PD-L1 highly expressed and 9 pts were considered as expressed. Eight pts were assessed as TMB-high. Five pts with PD-L1 negative expression were TMB-high, and 8 pts with TMB-low were PD-L1 positive expression. TMB and PD-L1 expression are independent indicators with the spearman r of 0.01 (p = 0.96). Conclusions: The detection rate of germline and somatic mutations in HRR genes were 27.3% and 36.5-40%, respectively, which defined a large number of ovarian cancer pts who can benefit from PARPi. PD-L1 expression and TMB are independent biomarkers, which may be combined to predict the efficacy of immunotherapy in future exploratory trials.

Rate of incidental germline findings detected by tumor-normal matched sequencing in cancer types lacking hereditary cancer testing guidelines.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10582-10582
Author(s):  
Timothy A. Yap ◽  
Arya Ashok ◽  
Jessica Stoll ◽  
Anna Ewa Schwarzbach ◽  
Kimberly L. Blackwell ◽  
...  
Keyword(s):  
Bile Duct ◽  
Hereditary Cancer ◽  
Next Generation Sequencing Data ◽  
Cancer Type ◽  
Cancer Genes ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Germline Variants ◽  
Cancer Types ◽  
Germline Testing

10582 Background: Up to 10% of all cancers are associated with hereditary cancer syndromes; however, guidelines for germline testing are currently limited to patients and families with specific cancer types (ovarian, breast, prostate, pancreatic, etc.). Although germline alterations have been shown in genes associated with cancers such as bile-duct, head & neck, brain, bladder, esophageal, and lung cancers, genetic testing is not routinely offered (PMID: 28873162). In such cancers, a guidelines-based approach may fail to detect cancer risk variants found by tumor-normal (T/N) matched sequencing. Here, we report the prevalence of incidental germline findings in patients with the aforementioned 6 cancer types and highlight frequently mutated genes by cancer type. Methods: We retrospectively analyzed next-generation sequencing data from de-identified records of 19,630 patients tested using Tempus|xT T/N matched assay. Incidental germline findings (i.e., single nucleotide variants and small insertions/deletions) detected in 50 hereditary cancer genes were determined for: bile duct (n = 466), head & neck (n = 673), esophageal (n = 395), brain (n = 1,391), bladder (n = 810), and lung (n = 5,544), where n = total patients. For comparison, we also included 4 cancer types that frequently undergo germline testing: ovarian (n = 2,042), breast (n = 3,542), prostate (n = 2,146), and pancreatic (n = 2,621). Results: We detected incidental pathogenic/likely pathogenic germline variants (P/LPV) in 6.5% (601/9,279) of patients diagnosed with the 6 selected cancer types lacking hereditary cancer testing guidelines. The highest prevalence of P/LPV was identified in patients with bladder (8%), brain (6.9%), and lung (6.5%) cancers. Frequently mutated genes (Table) include ATM (n = 62), BRCA2 (n = 60), BRCA1 (n = 33), APC (n = 27), and CHEK2 (n = 21). Of note, the Ashkenazi Jewish variant (p.I1307K) was the most frequent mutation in APC. For cancer types where patients frequently undergo germline testing, the rates of incidental germline findings in descending order were ovarian (15%), breast (12%), prostate (9.4%), and pancreatic (8.5%) cancers. Conclusions: In addition to enhanced variant calling, T/N matched sequencing may identify germline variants missed by a guidelines-based approach to testing. The identification of such germline findings may have clinical implications for the patient, as well as at-risk family members, thereby resulting in the opportunity for genetic counseling and risk-stratified intervention.[Table: see text]

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