Author of

• 36095

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  OA11 - A Symphony of Progress (ID 229)

  • Event: WCLC 2020
  • Type: Oral
  • Track: Small Cell Lung Cancer/NET
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/31/2021, 15:30 - 16:30, Scientific Program Auditorium

  • 36098

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    OA11.05 - Whole Exome Sequencing Reveals the Potential Role of Hereditary Predisposition in Small Cell Lung Cancer, a Tobacco-Related Cancer (ID 1300)

    15:30 - 16:30  |  Presenting Author(s): Nobuyuki Takahashi
    • Abstract
    • Presentation
    • Slides

    Introduction
    

    Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance, especially in small cell lung cancer (SCLC), the most lethal lung cancer which is almost exclusively related to tobacco. Inherited susceptibility to SCLC and its association with clinical characteristics remain unknown.

    Methods
    

    We sequenced germline whole exomes of 87 patients (77 SCLC, 10 extrapulmonary small cell) and compared with an independent SCLC cohort, and cancer-free non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) cohort. We also evaluated clinical characteristics associated with the germline genotype.

    Results
    

    Among 607 cancer predisposition and SCLC-related genes, we discovered 42 deleterious variants in 35 genes among 38 (43.7%) of patients. Identification of variants influenced medical management and family member testing in 9 (10.3%) patients. Six germline mutations were also found in an independent cohort of 79 SCLC patients, including three of the same variants (MUTYH G386D, POLQ I421Rfs*7, and RNASEL E265X). By tumor whole exome sequencing we confirmed loss of heterozygosity of MLH1, BRCA2, and SMARCA4. Consistent with the contribution to potential cancer predisposition, patients with MLH1, BRCA2, and MUTYH mutations had personal and family history of cancer and lung cancers including SCLC. Germline RAD51D, CHEK1, BRCA2 and MUTYH mutations were more likely to be found in unselected SCLC patients in our cohort compared with ExAC cohort. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio, OR: 1.82, 2.60) and longer recurrence-free survival following platinum-based chemotherapy (p = 0.002), independent of known prognostic factors including sex, stage, and age at diagnosis.

    Conclusion
    

    This work demonstrates that SCLC may have an inherited predisposition and provide the first and most detailed picture yet of how differences germline genotype may put some individuals at greater risk. These findings lay the foundation for understanding the interaction between genotype and tobacco exposure in exacerbating SCLC risk and will have substantial implications for targeted therapies and directed cancer screening for patients and their families.

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