scholarly journals Clinical actionability of universal sequencing for germline cancer susceptibility gene mutations among patients with colorectal cancer: A prospective study.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 63-63
Author(s):  
Wu Jiang ◽  
Peirong Ding
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Hereditary Cancer Syndromes ◽  
Tailored Treatment ◽  
History Of ◽  
Cancer Susceptibility Gene ◽  
Cancer Syndromes

63 Background: Genetic predisposition is an important cause of colorectal cancer (CRC). Previous studies have demonstrated that universal sequencing in unselected CRC patients with multi-gene panel could detect more hereditary cancer syndromes. However, it is unclear whether this strategy would change clinical management for the affected individuals. Methods: We prospectively enrolled a consecutive cohort of 486 CRC patients, comprising of unselective patients aged no more than 70 years and patients older than 70 years with hereditary risk features. All participants received germline testing using a comprehensive panel of 81 genes associated with various hereditary cancer syndromes. Results: Fifty-two pathogenic or likely pathogenic mutations were discovered in 51 (10.5%, 51/486) patients, including 20 (4.1%) Lynch syndrome, 11 (4.1%) germline mutations with known CRC risk, and 20 (4.1%) in other cancer susceptibility genes not traditionally associated with CRC. Among them, 21 (4.3%) mutation-positive patients would have been left undiagnosed if they only adhered to present guidelines. Nearly seventy percent (36/51) of the mutation-positive patients were found to carry clinicalactionable germline mutations, for whom enhanced screening and/or tailored treatment was recommended.CRC location, multiple CRC diagnoses, personal history of malignancy, or family history of malignancy was not significantly related to the presence of a mutation in non-CRC susceptibility genes. Conclusions: Universal germline sequencing for cancer susceptibility gene among CRC patients substantially identified more individuals with hereditary cancer syndrome and actionable germline mutations, and these patients might benefit from enhanced surveillance and better tailored treatment. Clinical trial information: NCT03365986.

scholarly journals High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer

2015 ◽  
Vol 33 (31) ◽  
pp. 3544-3549 ◽  
Author(s):  
Maureen E. Mork ◽  
Y. Nancy You ◽  
Jun Ying ◽  
Sarah A. Bannon ◽  
Patrick M. Lynch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Counseling ◽  
Family History ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndrome ◽  
History Of ◽  
Cancer Syndromes ◽  
History Of Cancer

Purpose Established guidelines recommend evaluation for hereditary cancer syndromes in patients younger than 50 years diagnosed with colorectal cancer (CRC). This group has been well described in the literature; however, patients diagnosed as adolescents and young adults are not well represented in CRC studies. Here, we define the clinical profile, including the extent of hereditary cancer syndromes and family history of cancer, in patients diagnosed with CRC at age 35 or younger. Patients and Methods We reviewed patients who underwent genetic counseling at our institution during 5 years (2009 to 2013). Data were collected regarding demographics, clinicopathologic information, tumor and genetic testing, and family history. Patients with an identified hereditary cancer syndrome were compared with those without a syndrome. Results Of the 193 patients with evaluable data, 35% had an identifiable hereditary cancer syndrome, including 23 with Lynch syndrome, 22 with mutation-negative Lynch syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with biallelic MUTYH mutations, and one with Li-Fraumeni syndrome. Patients without a hereditary syndrome more frequently presented with metastatic disease, whereas patients with a syndrome were more likely to present at earlier stages and to have a family history of cancer. Nevertheless, a substantial proportion of the hereditary syndromes (19%) were diagnosed in individuals with no family history of the disease. Conclusion We conclude that patients diagnosed with CRC at age 35 years or younger should receive genetic counseling regardless of their family history and phenotype.

scholarly journals Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer

2017 ◽  
Vol 35 (10) ◽  
pp. 1086-1095 ◽  
Author(s):  
Matthew B. Yurgelun ◽  
Matthew H. Kulke ◽  
Charles S. Fuchs ◽  
Brian A. Allen ◽  
Hajime Uno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Mutations ◽  
Age At Diagnosis ◽  
Pathogenic Mutations ◽  
High Penetrance ◽  
History Of ◽  
Cancer Susceptibility Gene

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel

2021 ◽  
pp. jmedgenet-2020-107230
Author(s):  
Wu Jiang ◽  
Lin Li ◽  
Chuan-Feng Ke ◽  
Wei Wang ◽  
Bin-Yi Xiao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Hereditary Cancer Syndromes ◽  
Cancer Susceptibility Genes ◽  
Additional Testing ◽  
Cancer Syndromes ◽  
Germline Testing ◽  
Testing Set

PurposeUniversal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.MethodsWe prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.ResultsThe prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.ConclusionUniversal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.Trial registration numberNCT03365986.

Familial cancer syndromes and genetic counselling

2016 ◽  
pp. 276-290
Author(s):  
Henry T. Lynch ◽  
Carrie L. Snyder ◽  
Jane F. Lynch
Keyword(s):  
Colorectal Cancer ◽  
Molecular Genetics ◽  
Genetic Counselling ◽  
Hereditary Cancer ◽  
Genetic Model ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Clinical Genetic ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Thanks to the veritably logarithmic advances in the molecular genetics of many emerging hereditary cancer syndromes, genetic counselling has become of paramount importance. It is a key element of the emerging concepts for patient education and management, which have become the clinical bedrock for diagnosis and management of hereditary cancer. Genetic counsellors have become proficient in the understanding of the complexities of molecular genetics in relation to hereditary cancer syndromes, demonstrating their ability both to supplement and replace the customary physician’s role in this overall process. We have used colorectal cancer, in particular Lynch syndrome, as a clinical genetic model based on the authors’ experience with diagnosis, DNA testing, and counselling of thousands of families for over four decades. Undoubtedly, the surface of the proverbial iceberg has barely been grazed in regard to the developments for the genetic counseling discipline.

scholarly journals Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

2019 ◽  
Vol 37 (13) ◽  
pp. 1070-1080 ◽  
Author(s):  
Toshiya Abe ◽  
Amanda L. Blackford ◽  
Koji Tamura ◽  
Madeline Ford ◽  
Patrick McCormick ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Germline Mutation ◽  
Cancer Susceptibility ◽  
Risk Group ◽  
Susceptibility Gene ◽  
Familial Risk ◽  
Germline Mutations ◽  
Neoplastic Progression ◽  
Cancer Susceptibility Gene

PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

Landscape of germline mutations in 1144 patients (Pts) with gastrointestinal (GI) cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13660-e13660
Author(s):  
Mohamed E. Salem ◽  
Lisa Amacker-North ◽  
Mariah Gleason ◽  
Aly Athens ◽  
William Mills Worrilow ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Checkpoint Inhibitors ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Gene Panel ◽  
Variant Of Uncertain Significance ◽  
Gi Cancer ◽  
Germline Testing

e13660 Background: The efficacy of PARP inhibitors in germline BRCA-mutated pancreatic adenocarcinoma (PC) and immune checkpoint inhibitors in dMMR colorectal cancer (CRC) shows the importance of genetic testing. We aimed to characterize the frequency of pathogenic/likely pathogenic germline variants (PLPVs) in GI cancer pts. Methods: A retrospective review of pts referred to the Levine Cancer Institute Genetics Program was conducted. Genetic testing used a focused hereditary cancer 4-43 gene panel or pan-cancer 82-84 gene panel. Results: Out of 1144 GI cancer pts seen between 2010 and 2019, 869 underwent germline testing, and 199 (23%) pts had at least one PLPV in a hereditary cancer susceptibility gene, while 253 (29.3%) had a variant of uncertain significance. Of 630 CRC pts, 24% had a PLPV and 13% harbored a germline mutation in DNA MMR genes and were diagnosed with Lynch Syndrome, representing ~50% of all pts with a PLPV. Other germline PLPVs were found in APC, ATM, BRCA1, BRCA2, CHEK2, MUTYH, and PALB2. Of 163 PC pts, 16.6% had a PLPV in ATM, BRCA2, CDKN2A, and MEN1. Gastric cancer pts (17%) had germline PLPVs in APC, BRCA2, CDH1, MLH1, and MSH2; biliary cancer pts (17%) had germline PLPVs in PALB2, RAD50, and PTCH1; and GIST pts (60%) had PLPVs in SDHA or SDHB. Conclusions: Germline mutations were found in 23% of GI cancer pts, underlining the importance of multigene germline testing. Knowledge of inherited GI cancer risk helps determine the likelihood of benefit from possible specific targeted therapies. Genetic testing and counseling pose a challenge, but implications for pts with hereditary syndromes are highly significant. [Table: see text]

scholarly journals Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients—a Systematic Review

2017 ◽  
Vol 152 (1) ◽  
pp. 75-77.e4 ◽  
Author(s):  
Peter Broderick ◽  
Sara E. Dobbins ◽  
Daniel Chubb ◽  
Ben Kinnersley ◽  
Malcolm G. Dunlop ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Systematic Review ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Variants ◽  
Cancer Susceptibility Gene
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