Lung cancer predisposition in women with previous breast cancer identified by whole exome sequencing

Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

Download Full-text

Identification of new breast cancer predisposition genes via whole exome sequencing

Hereditary Cancer in Clinical Practice ◽

10.1186/1897-4287-10-s2-a40 ◽

2012 ◽

Vol 10 (Suppl 2) ◽

pp. A40

Author(s):

MC Southey ◽

DJ Park ◽

F Lesueur ◽

F Odefrey ◽

T Nguyen-Dumont ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cancer Predisposition ◽

Breast Cancer Predisposition ◽

Whole Exome ◽

Predisposition Genes

Download Full-text

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy

JCO Precision Oncology ◽

10.1200/po.19.00354 ◽

2020 ◽

pp. 1109-1121

Author(s):

Bryan P. Schneider ◽

Leigh Anne Stout ◽

Santosh Philips ◽

Courtney Schroeder ◽

Susanna F. Scott ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Metastatic Cancer ◽

Cohort Analysis ◽

Cancer Predisposition ◽

Whole Exome ◽

Germline Variation ◽

Tumor Types ◽

Cancer Predisposition Gene

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

Download Full-text

Faculty Opinions recommendation of Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739435020.793584369 ◽

2021 ◽

Author(s):

Julien Sage

Keyword(s):

Lung Cancer ◽

Dna Repair ◽

Small Cell Lung Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Whole Exome ◽

Cancer Subtype

Download Full-text

Whole Exome Sequencing of Simultaneous Primary Multifocal Lung Cancer (SMPLC): Case Report and Bioinformatics Analysis

10.21203/rs.3.rs-96042/v1 ◽

2020 ◽

Author(s):

Donglin Zhu ◽

Minghong Shen ◽

Jinghuan Lv

Keyword(s):

Lung Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Bioinformatics Analysis ◽

Clonal Evolution ◽

Evolutionary Relationship ◽

Primary Lung Cancer ◽

The Cancer Genome Atlas ◽

Control Group ◽

Whole Exome

Abstract Background: To understand the molecular mechanism of synchronous multifocal lung cancer (SMLC) is of great significance for the differential diagnosis of intrapulmonary metastasis (IM) and synchronous multiple primary lung cancer (SMPLC). Recently, next-generation sequencing (NGS) has become a useful tool for understanding SMLC. Case presentation: In this study, two lesions of a 61-year-old man with lung cancer were detected by whole exome sequencing (WES) and the correlation between different lesions was analyzed at the molecular level. Lesion 1 was adenocarcinoma and lesion 2 was squamous cell carcinoma. Gene mutation and copy number variation (CNV) are different in the two lesions. The genome of lesion 2 is more unstable. The clonal evolution analysis showed that there was no obvious evolutionary relationship between the two lesions, and both lesions were independent double primary lesions. Bioinformatics analysis revealed that the alternate genes of the two lesions were inconsistent in function and pathway. PCA analysis was performed using the Cancer Genome Atlas (TCGA) database and the GTEx database, and it was found that the changed genes in these two lesions were significantly separated from the control group, and the changes of TP53 and EGFR genes in the TCGA database were further described. Conclusions: These results indicate that NGS may provide new ideas for SMLC classification.

Download Full-text

Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

Problems in oncology ◽

10.37469/0507-3758-2021-67-1-111-116 ◽

2021 ◽

Vol 67 (1) ◽

pp. 111-116

Author(s):

Kirill Zagorodnev ◽

Aleksandr Romanko ◽

Uliy Gorgul ◽

Aleksandr Ivantsov ◽

Anna Sokolenko ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Hereditary Breast Cancer ◽

Germ Line ◽

Genetic Diagnosis ◽

Clinical Signs ◽

Causative Mutation ◽

Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

Download Full-text