Case‐case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

2021 ◽  
Author(s):  
Sharon E. Johnatty ◽  
Tina Pesaran ◽  
Jill Dolinsky ◽  
Amal Yussuf ◽  
Holly La Duca ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Case Analysis ◽  
Ascertainment Bias ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
Multigene Panel

scholarly journals Multigene Panel Testing Provides a New Perspective on Lynch Syndrome

2017 ◽  
Vol 35 (22) ◽  
pp. 2568-2575 ◽  
Author(s):  
Carin R. Espenschied ◽  
Holly LaDuca ◽  
Shuwei Li ◽  
Rachel McFarland ◽  
Chia-Ling Gau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Population Based ◽  
Brca1 And Brca2 ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
New Perspective ◽  
Testing Criteria ◽  
Multigene Panel

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

scholarly journals Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

2021 ◽  
pp. 1588-1602
Author(s):  
Monica D. Levine ◽  
Rachel Pearlman ◽  
Heather Hampel ◽  
Casey Cosgrove ◽  
David Cohn ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Type Ii ◽  
Newly Diagnosed ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

scholarly journals Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome

2020 ◽  
Author(s):  
Tomoko Yoshihama ◽  
Akira Hirasawa ◽  
Kokichi Sugano ◽  
Teruhiko Yoshida ◽  
Mineko Ushiama ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Pathogenic Variant ◽  
Clinical Settings ◽  
Bilateral Oophorectomy ◽  
Panel Testing ◽  
History Of ◽  
Multigene Panel Testing ◽  
Multigene Panel

Abstract There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

Application of Multigene Panel Testing In Patients With High Risk for Hereditary Colorectal Cancer

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Ji Soo Park ◽  
Jung Won Park ◽  
Saeam Shin ◽  
Seung-Tae Lee ◽  
Sang Joon Shin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
High Risk ◽  
Hereditary Colorectal Cancer ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
Multigene Panel

Informing models of cancer genetic care in the era of multigene panel testing with patient‐led recommendations

2020 ◽  
Author(s):  
Meghan Underhill‐Blazey ◽  
Traci Blonquist ◽  
Anu Chittenden ◽  
Rachel Pozzar ◽  
Manan Nayak ◽  
...  
Keyword(s):  
Cancer Genetic ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
Multigene Panel
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