Browsing by Author "McDuffie, Lucas A."

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    Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)
    (BMJ, 2019-06) Lo, Winifred; Zhu, Bin; Sabesan, Arvind; Wu, Ho-Hsiang; Powers, Astin; Sorber, Rebecca A.; Ravichandran, Sarangan; Chen, Ina; McDuffie, Lucas A.; Quadri, Humair S.; Beane, Joal D.; Calzone, Kathleen; Miettinen, Markku M.; Hewitt, Stephen M.; Koh, Christopher; Heller, Theo; Wacholder, Sholom; Rudloff, Udo; Surgery, School of Medicine
    INTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.
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    Identification of Neoantigen-Reactive Tumor-Infiltrating Lymphocytes in Primary Bladder Cancer
    (American Association of Immunologists, 2019-06-15) Leko, Vid; McDuffie, Lucas A.; Zheng, Zhili; Gartner, Jared J.; Prickett, Todd D.; Apolo, Andrea B.; Agarwal, Piyush K.; Rosenberg, Steven A.; Lu, Yong-Chen; Surgery, School of Medicine
    Immune checkpoint inhibitors (ICIs) are effective in treating a variety of malignancies, including metastatic bladder cancer. A generally accepted hypothesis suggests that ICIs induce tumor regressions by reactivating a population of endogenous tumor-infiltrating lymphocytes (TILs) that recognize cancer neoantigens. Although previous studies have identified neoantigen-reactive TILs from several types of cancer, no study to date has shown whether or not neoantigen-reactive TILs can be found in bladder tumors. To address this, we generated TIL cultures from patients with primary bladder cancer and tested their ability to recognize tumor-specific mutations. We found that CD4+ TILs from one patient recognized mutated C-terminal binding protein 1 (CTBP1Q277R) in an MHC class II-restricted manner. This finding suggests that neoantigen-reactive TILs reside in bladder cancer, which may help explain the effectiveness of immune checkpoint blockade in this disease, and also provides a rationale for the future use of adoptive T-cell therapy targeting neoantigens in bladder cancer.
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    Successful treatment of a solitary skull metastasis in a child with Wilms' Tumor
    (Elsevier, 2017-07) McDuffie, Lucas A.; Fallon, Robert J.; Vik, Terry A.; Billmire, Deborah F.; Medicine, School of Medicine
    This report presents the successful treatment of a child with a solitary metastatic lesion to the calvarium following treatment for Stage III anaplastic Wilms’ Tumor.