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

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.

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

International Cancer Conference Journal ◽

10.1007/s13691-020-00449-9 ◽

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.

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Effect of access to germline genetic testing on pancreatic cancer precision treatment across disease stage and ethnicity.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16783 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16783-e16783

Author(s):

Edward D. Esplin ◽

Rebecca Truty ◽

Shan Yang ◽

Sarah M. Nielsen ◽

Margaret Klint ◽

...

Keyword(s):

Pancreatic Cancer ◽

African American ◽

Genetic Testing ◽

Family History ◽

Germline Mutations ◽

Disease Stage ◽

Family History Of Cancer ◽

History Of ◽

History Of Cancer ◽

Multigene Panel

e16783 Background: PARP inhibitor (PARPi) treatment was recently approved for pancreatic cancer (PaCa) patients with germline mutations in 2 DNA damage repair (DDR) genes. Despite criteria recommending germline multigene panel testing for all PaCa patients, barriers to testing remain, including among underserved populations, which limit access to precision therapies. We initiated a sponsored testing program that increases access to germline genetic testing for PaCa in two ways: 1) offering a comprehensive multigene panel, and 2) removing the barrier of cost. Here we present initial results from this program, including the diagnostic yield in patients across stages of PaCa and clinical utility of the findings. Methods: We retrospectively analyzed de-identified data from 966 PaCa patients tested on an 84 gene panel as part of the program to date. The only inclusion criterion was a willingness to participate in the sponsored program by the patient and the provider who ordered the testing. Data included likely pathogenic (LP) and pathogenic (P) mutations, disease stage and ethnicity. Results: In total, 166 (17%) patients were positive for P/LP germline mutations in 30 genes. Mutation rate by ethnicity was: Caucasian 17%, African American 12%, Hispanic 16%, Ashkenazi Jewish 20%, Asian 3%. Only 25% of patients with P/LP variants reported a family history of cancer. There was no statistical difference in mutation rates by stage (p = 0.11) [Table]. In positive patients, 83 (78%) had mutations conferring potential eligibility for DDR gene-specific precision therapies or clinical treatment trials. 28 (26%) were potentially eligible for olaparib due to BRCA1/2 mutations, 8 (7%) were potentially eligible for pembrolizumab, and 47 (44%) for PARPi clinical trials. Conclusions: This study found 8.5% of all PaCa patients tested are potentially eligible for germline-based precision therapies and/or clinical treatment trials. Of mutation positive patients, 75% did not report a family history of cancer. The positive rate was not statistically different between patients with stage I and stage IV PaCa, underscoring the recommendation to test all patients with PaCa. This program had a 1.5% increased relative uptake among African American patients compared to a standard insurance reimbursement delivery model. These data suggest reducing barriers improves PaCa patient access to genetic information that enables precision therapy. [Table: see text]

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Racial/Ethnic Differences in the Association Between Family History of Cancer and Smoking Status Among US Adults

Annals of Epidemiology ◽

10.1016/j.annepidem.2020.08.025 ◽

2020 ◽

Vol 52 ◽

pp. 103-104

Author(s):

I. Jackson ◽

K. Okhawere ◽

G. Oboli ◽

A. Opiegbe ◽

O. Eromosele

Keyword(s):

Family History ◽

Ethnic Differences ◽

Smoking Status ◽

Family History Of Cancer ◽

History Of ◽

Racial Ethnic ◽

History Of Cancer

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Family history of cancer in first degree relatives and risk of cancer of unknown primary

European Journal of Cancer Care ◽

10.1111/ecc.13485 ◽

2021 ◽

Author(s):

Alexander L. R. Grewcock ◽

Karlijn E. P. E. Hermans ◽

Matty P. Weijenberg ◽

Piet A. Brandt ◽

Caroline Loef ◽

...

Keyword(s):

Family History ◽

Cancer Of Unknown Primary ◽

Unknown Primary ◽

Family History Of Cancer ◽

First Degree Relatives ◽

History Of ◽

Risk Of Cancer ◽

History Of Cancer

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Clinical, Pathological and Molecular Characteristics of Chilean Patients with Early-, Intermediate- and Late-Onset Colorectal Cancer

Cells ◽

10.3390/cells10030631 ◽

2021 ◽

Vol 10 (3) ◽

pp. 631

Author(s):

Karin Alvarez ◽

Alessandra Cassana ◽

Marjorie De La Fuente ◽

Tamara Canales ◽

Mario Abedrapo ◽

...

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Age Of Onset ◽

Late Onset ◽

Molecular Characteristics ◽

Family History Of Cancer ◽

Molecular Features ◽

Age Of Diagnosis ◽

History Of ◽

History Of Cancer

Colorectal cancer (CRC) is the second most frequent neoplasm in Chile and its mortality rate is rising in all ages. However, studies characterizing CRC according to the age of onset are still lacking. This study aimed to identify clinical, pathological, and molecular features of CRC in Chilean patients according to the age of diagnosis: early- (≤50 years; EOCRC), intermediate- (51–69 years; IOCRC), and late-onset (≥70 years; LOCRC). The study included 426 CRC patients from Clinica Las Condes, between 2007 and 2019. A chi-square test was applied to explore associations between age of onset and clinicopathological characteristics. Body Mass Index (BMI) differences according to age of diagnosis was evaluated through t-test. Overall (OS) and cancer-specific survival (CSS) were estimated by the Kaplan–Meier method. We found significant differences between the age of onset, and gender, BMI, family history of cancer, TNM Classification of Malignant Tumors stage, OS, and CSS. EOCRC category was characterized by a family history of cancer, left-sided tumors with a more advanced stage of the disease but better survival at 10 years, and lower microsatellite instability (MSI), with predominant germline mutations. IOCRC has shown clinical similarities with the EOCRC and molecular similarities to the LOCRC, which agrees with other reports.

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