Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing

Background: Recent advances in next-generation sequencing (NGS) technology have enabled multigene testing and changed the diagnostic approach to hereditary gastrointestinal cancer/polyposis syndromes. The aim of this study was to analyze different cancer predisposition genes in hereditary/sporadic gastrointestinal cancer/polyposis. Methods: Cancer predisposition genes were analyzed with an Illumina MiSeq NGS system in 80 patients with gastrointestinal cancer/polyposis who were examined between the years 2016 and 2019. Deletion/duplication analysis of MLH1, MSH2, and EPCAM genes was performed by using the multiplex ligation-dependent probe amplification method. Results: Germline testing of hereditary cancer-related genes was performed in 80 patients with gastrointestinal cancer/polyposis. A total of 30 variants in 30 cases (37.5%) were assessed as pathogenic/likely pathogenic. A total of 19 heterozygous variants were assessed as variants of uncertain clinical significance in 17 cases (21.25%) and 18 (22.5%) novel variations (9 pathogenic/likely pathogenic, 9 variants of uncertain significance) were determined. In 4 (5%) cases, multiplex ligation-dependent probe amplification detected deletions in MLH1, MSH2, and EPCAM genes. Conclusion: The accumulation of analyses with multigene testing will increase the available data for cancer predisposition genes in hereditary gastrointestinal cancer/polyposis. Educational campaigns for prevention, efficient screening programs, and more personalized care based on the profile of individual patients are necessary.

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Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

JCO Precision Oncology ◽

10.1200/po.18.00338 ◽

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.

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Targeted next generation sequencing identifies somatic mutations in a cohort of Egyptian breast cancer patients

Journal of Advanced Research ◽

10.1016/j.jare.2020.04.001 ◽

2020 ◽

Vol 24 ◽

pp. 149-157

Author(s):

Auhood Nassar ◽

Mohamed Abouelhoda ◽

Osman Mansour ◽

Samah A. Loutfy ◽

Mohamed M. Hafez ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Cancer Patients ◽

Somatic Mutations ◽

Next Generation ◽

Breast Cancer Patients ◽

Targeted Next Generation Sequencing ◽

Generation Sequencing

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The Genetic Germline Background of Single and Multiple Primary Melanomas

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.555630 ◽

2021 ◽

Vol 7 ◽

Author(s):

Simona De Summa ◽

Antonia Lasorella ◽

Sabino Strippoli ◽

Giuseppe Giudice ◽

Gabriella Guida ◽

...

Keyword(s):

Next Generation Sequencing ◽

Cell Cycle Control ◽

Germline Mutations ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Multiple Genes ◽

Multiple Primary ◽

Small Cohort ◽

Sequencing Platforms ◽

Generation Sequencing

Background:Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing panel.Materials and Methods:A total of 39 patients, 20 with SPM and 19 with MPM, were enrolled in our study. Next generation analysis was carried out using a custom targeted sequencing panel that included 32 genes known to have a role in several carcinogenic pathways, such as those involved in DNA repair, pigmentation, regulation of kinases, cell cycle control and senescence.Results:We found a significant correlation between PIK3CA:p.I391M and MPMs, compared to SPMs,p= 0.031 and a trend for the association between CYP1B1: p.N453S and SPMs, compared to MPMs (p= 0.096). We also found that both subgroups shared a spectrum of 9 alterations in 8 genes (CYP1B1: p.N453S, BAP1: p.C39fs, PIK3CA: p.I391M, CDKAL1: c.1226_1227TG, POLE: p.V1161fs, OCA2: p.R419Q, OCA2: p.R305W, MC1R: p.V60L, MGMT: p.L115F), which suggested that these genes may play a role in melanoma development.Conclusions:In conclusion, despite the small cohort of patients, we found that germline mutations, such as those of PIK3CAand CYP1B1, might contribute to the differential development of SPM and MPM.

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