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.

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 Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort

2019 ◽  
Vol 22 (4) ◽  
pp. 701-708 ◽  
Author(s):  
Hongyan Li ◽  
Holly LaDuca ◽  
Tina Pesaran ◽  
Elizabeth C. Chao ◽  
Jill S. Dolinsky ◽  
...  
Keyword(s):  
Family History ◽  
In Silico ◽  
Functional Domains ◽  
Family History Of Cancer ◽  
Panel Testing ◽  
History Of ◽  
Multigene Panel Testing ◽  
History Of Cancer ◽  
Multigene Panel

Abstract Purpose Genetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants. Methods We analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions. Results Twenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign. Conclusion The evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.

PTEN Promoter Variants Are Not Associated With Common Cancers: Implications for Multigene Panel Testing

2017 ◽  
pp. 1-7 ◽  
Author(s):  
Mary Helen Black ◽  
Shuwei Li ◽  
Tina Pesaran ◽  
Holly LaDuca ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Personal History ◽  
Variants Of Unknown Significance ◽  
Panel Testing ◽  
Multiple Primary ◽  
Unknown Significance ◽  
Uterine Endometrial Cancer ◽  
History Of ◽  
Race Ethnicity ◽  
Multigene Panel Testing ◽  
Multigene Panel

Purpose PTEN mutations are associated with breast, colon, endometrial, kidney, and thyroid cancers. Most PTEN promoter alterations, however, are characterized as variants of unknown significance, and their contribution to cancer risk is unclear. Materials and Methods Personal and family histories of 88,333 patients undergoing PTEN analysis as part of multigene panel testing (MGPT) were retrospectively reviewed. Cases (n = 59,784) were individuals with personal history of PTEN-related cancer. Controls (n = 28,549) had no personal history of cancer. Individuals were categorized as positive for one or more mutations (PATHO), without mutations but carrying one or more promoter variant (PROM), or negative for alterations (WT). Multivariable logistic regression was used to assess PTEN associations with phenotypes, adjusted for race/ethnicity, age, sex, and MGPT. Results Overall, 79 (0.09%) patients were PATHO and 791 (0.9%) were PROM carriers. Compared with WT, PATHOs were 2.30 (95% CI, 1.19 to 4.72) times as likely to have breast, 7.23 (95% CI, 2.74 to 19.14) times as likely to have bilateral/multiple primary breast, and 7.56 (95% CI, 1.97 to 23.98) times as likely to have uterine/endometrial cancer. PROMs were not significantly more likely than WT to have cancer (all 0.84 < odds ratio < 1.15; P > .05). Conclusion PTEN promoter variants were not associated with cancer. These results do not support the inclusion of PTEN promoter sequencing in MGPT.

Multigene panel testing in patients suspected to have Lynch syndrome.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 1509-1509 ◽  
Author(s):  
Matthew B. Yurgelun ◽  
Brian Allen ◽  
Rajesh R. Kaldate ◽  
Karla Bowles ◽  
Benjamin Roa ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Panel Testing ◽  
Multigene Panel Testing ◽  
Multigene Panel

Incidence and epigenetic factors associated with endometrial cancer in Appalachian Kentucky.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17113-e17113
Author(s):  
Rohini Manda ◽  
Naga Praneeth Raja ◽  
Uday Shankar ◽  
Mark Dignan ◽  
Nagapavani Kandagari
Keyword(s):  
Endometrial Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Age At Diagnosis ◽  
Epigenetic Factors ◽  
Family History Of Cancer ◽  
The Us ◽  
Appalachian Kentucky ◽  
History Of ◽  
History Of Cancer

e17113 Background: Data from the US Cancer Statistics Working Group shows that the age-adjusted incidence of endometrial cancer was 25.6/100,000, 2009-2013 for the US and 24.9/100,000 for the Commonwealth of Kentucky. However, for the Kentucky River Area Development District (KR) in the Appalachian region, the rate was higher at 34.2/100,000. This investigation was designed to explore epigenetic factors related to the elevated incidence of endometrial cancer in the KR region of Kentucky. Methods: With IRB approval, retrospective data on women with endometrial cancer were abstracted from tumor registry records for the period 2005-2015. Data including age at diagnosis, family history of cancer, smoking, diabetes and demographic characteristics were analyzed using SPSS. Results: Data on 41 cases of endometrial cancer from 2005-2015 were included in the analyses. The age range was 37-87 with mean age 62. Of the 41 cases, 19.5% (8/41) were under age 50 at diagnosis. 2 out of 8 (25%) had family history of Lynch syndrome associated malignancies. 9 (22.0%) had family history of cancer. No significant associations between smoking, age at diagnosis and diabetes were noted. Conclusions: There is an increased incidence of endometrial carcinoma in Appalachian Kentucky in general, and elevated rates in women under age 50 compared to statewide and US rates. We have shown from our previous research that there is a higher incidence of lynch syndrome among young patients with colon cancer in Appalachian Kentucky. Similar findings were observed with endometrial cancer from this analysis. Further evaluation and genetic testing for any association with Lynch syndrome in this age group is needed.

scholarly journals No Evidence of Increased Risk of Breast Cancer in Women With Lynch Syndrome Identified by Multigene Panel Testing

2020 ◽  
pp. 51-60 ◽  
Author(s):  
Jessica Stoll ◽  
Eric Rosenthal ◽  
Shelly Cummings ◽  
Jamie Willmott ◽  
Ryan Bernhisel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lynch Syndrome ◽  
Large Cohort ◽  
Average Risk ◽  
Female Population ◽  
Panel Testing ◽  
Increased Risk ◽  
Cancer Rates ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing. METHODS MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication. RESULTS In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30). CONCLUSION In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS.

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
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