scholarly journals Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes

2019 ◽  
Vol 145 (5) ◽  
pp. 1290-1298 ◽  
Author(s):  
Wenjuan Tian ◽  
Rui Bi ◽  
Yulan Ren ◽  
Hongsheng He ◽  
Shanfu Shi ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
High Frequency ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Hereditary Cancers ◽  
Predisposition Genes

scholarly journals Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

2019 ◽  
pp. 1-15
Author(s):  
Karen A. Cadoo ◽  
Diana L. Mandelker ◽  
Semanti Mukherjee ◽  
Carolyn Stewart ◽  
Deborah DeLair ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Next Generation Sequencing ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Predisposition ◽  
Next Generation ◽  
Germline Variants ◽  
Predisposition Genes ◽  
Generation Sequencing

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

scholarly journals Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sock Hoai Chan ◽  
Weng Khong Lim ◽  
Nur Diana Binte Ishak ◽  
Shao-Tzu Li ◽  
Wei Lin Goh ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Cancer Predisposition ◽  
Predisposition Genes

scholarly journals Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer

2015 ◽  
Vol 148 (3) ◽  
pp. 556-564 ◽  
Author(s):  
Robert C. Grant ◽  
Iris Selander ◽  
Ashton A. Connor ◽  
Shamini Selvarajah ◽  
Ayelet Borgida ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Predisposition Genes

scholarly journals Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

JAMA ◽  
2018 ◽  
Vol 319 (23) ◽  
pp. 2401 ◽  
Author(s):  
Chunling Hu ◽  
Steven N. Hart ◽  
Eric C. Polley ◽  
Rohan Gnanaolivu ◽  
Hermela Shimelis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Predisposition Genes

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 Germline mutations of renal cancer predisposition genes and clinical relevance in Chinese patients with sporadic, early‐onset disease

Cancer ◽  
2018 ◽  
Vol 125 (7) ◽  
pp. 1060-1069 ◽  
Author(s):  
Junlong Wu ◽  
Hongkai Wang ◽  
Christopher J. Ricketts ◽  
Youfeng Yang ◽  
Maria J. Merino ◽  
...  
Keyword(s):  
Renal Cancer ◽  
Early Onset ◽  
Clinical Relevance ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Chinese Patients ◽  
Predisposition Genes
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