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.

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]

scholarly journals Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing

2018 ◽  
Vol 36 (35) ◽  
pp. 3459-3465 ◽  
Author(s):  
Thomas P. Slavin ◽  
Kimberly C. Banks ◽  
Darya Chudova ◽  
Geoffrey R. Oxnard ◽  
Justin I. Odegaard ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Germline Mutations ◽  
Circulating Tumor Dna ◽  
Cancer Predisposition ◽  
Cancer Genetic Counseling ◽  
Predisposition Genes ◽  
Average Patient ◽  
Cancer Types ◽  
Tumor Dna ◽  
Hereditary Cancer Predisposition

Purpose To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation. Patients and Methods Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes. Results More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described. Conclusion Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.

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

2016 ◽  
Vol 34 (13) ◽  
pp. 1460-1468 ◽  
Author(s):  
Nadine Tung ◽  
Nancy U. Lin ◽  
John Kidd ◽  
Brian A. Allen ◽  
Nanda Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Triple Negative ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Ashkenazi Jewish ◽  
Breast Cancer Predisposition ◽  
Cancer Susceptibility Genes ◽  
Predisposition Genes

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

scholarly journals Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes

2018 ◽  
pp. 1-28 ◽  
Author(s):  
Chunling Hu ◽  
Holly LaDuca ◽  
Hermela Shimelis ◽  
Eric C. Polley ◽  
Jenna Lilyquist ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
High Risk ◽  
Hereditary Cancer ◽  
Odds Ratio ◽  
Cancer Predisposition ◽  
Moderate Risk ◽  
Cancer Susceptibility Genes ◽  
Predisposition Genes ◽  
History Of

Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population. Methods Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed. Results The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer. Conclusion These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.

A surveillance clinic for children and adolescents with, or at risk of, hereditary cancer predisposition syndromes

2021 ◽  
Vol 214 (7) ◽  
pp. 335
Author(s):  
Nicholas Leedman ◽  
Murray Princehorn ◽  
Nicholas Gottardo ◽  
Claire Franklin ◽  
Rebecca D'Souza ◽  
...  
Keyword(s):  
At Risk ◽  
Children And Adolescents ◽  
Hereditary Cancer ◽  
Cancer Predisposition ◽  
Hereditary Cancer Predisposition

scholarly journals Cancer Risk Assessment and Screening; A Challenge for Clinical Pathology Service?

2020 ◽  
Vol 27 (1) ◽  
Author(s):  
Siti Boedina Kresno
Keyword(s):  
Risk Factors ◽  
Cancer Risk ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Intrinsic Factor ◽  
Cancer Risk Assessment ◽  
Prophylactic Surgery ◽  
Cancer Etiology ◽  
Cancer Burden ◽  
Cancer Susceptibility Genes

There is evidence demonstrating that cancer etiology is multi-factorial and modification of risk factors has achievedcancer prevention. There is therefore a need to advance the understanding of cancer etiology through interaction effectsbetween risk factors when estimating the contribution of an individual to the cancer burden in a population. It has beenknown that cancer may arise from genetic susceptibility to the disease as an intrinsic factor; however, non-intrinsic factorsdrive most cancer risk as well and highlight the need for cancer prevention. Are our clinical pathologists aware of thesefacts?. Are they ready to understand and to provide an excellent test with good expertise?. Hereditary cancer testing istypically performed using gene panels, which may be either cancer-specific or pan-cancer to assess risk for a defined orbroader range of cancers, respectively. Given the clinical implications of hereditary cancer testing, diagnostic laboratoriesmust develop high-quality panel tests, which serve a broad, genetically diverse patient population. The result will determinea patient's eligibility for targeted therapy, for instance, or lead a patient to prophylactic surgery, chemoprevention, andsurveillance. This review will introduce the definitions of intrinsic and non-intrinsic risk factors, which have been employed inrecent work and how evidence for their effects on the cancer burden in human subjects has been obtained. Genetic testingof cancer susceptibility genes by use of liquid biopsies and New Generation Sequencing (NGS) is now widely applied inclinical practice to predict the risk of developing cancer, help diagnosis, and treatment monitoring.

Utilization of Multigene Panels in Hereditary Cancer Predisposition Testing

2015 ◽  
pp. 459-482
Author(s):  
Holly LaDuca ◽  
Tina Pesaran ◽  
Aaron M. Elliott ◽  
Virginia Speare ◽  
Jill S. Dolinsky ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Cancer Predisposition ◽  
Multigene Panels ◽  
Hereditary Cancer Predisposition
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