Melbourne School of Population and Global Health - Research Publications

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Author: Hopper, John × Type: Preprint ×

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    A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.
    Walker, R ; Mahmood, K ; Joo, JE ; Clendenning, M ; Georgeson, P ; Como, J ; Joseland, S ; Preston, SG ; Antill, Y ; Austin, R ; Boussioutas, A ; Bowman, M ; Burke, J ; Campbell, A ; Daneshvar, S ; Edwards, E ; Gleeson, M ; Goodwin, A ; Harris, MT ; Henderson, A ; Higgins, M ; Hopper, JL ; Hutchinson, RA ; Ip, E ; Isbister, J ; Kasem, K ; Marfan, H ; Milnes, D ; Ng, A ; Nichols, C ; O'Connell, S ; Pachter, N ; Pope, BJ ; Poplawski, N ; Ragunathan, A ; Smyth, C ; Spigelman, A ; Storey, K ; Susman, R ; Taylor, JA ; Warwick, L ; Wilding, M ; Williams, R ; Win, AK ; Walsh, MD ; Macrae, FA ; Jenkins, MA ; Rosty, C ; Winship, IM ; Buchanan, DD ; Family Cancer Clinics of Australia, ( 2023-03-01)
    Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
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    Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.
    Morra, A ; Schreurs, MAC ; Andrulis, IL ; Anton-Culver, H ; Augustinsson, A ; Beckmann, MW ; Behrens, S ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Broeks, A ; Buys, SS ; Camp, NJ ; Castelao, JE ; Cessna, MH ; Chang-Claude, J ; Chung, WK ; Collaborators, N ; Colonna, SV ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Dennis, J ; Devilee, P ; Dörk, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fehm, TN ; Figueroa, JD ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; García-Closas, M ; García-Sáenz, JA ; Genkinger, J ; Grassmann, F ; Gündert, M ; Hahnen, E ; Haiman, CA ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hoppe, R ; Hopper, JL ; Houlston, RS ; Howell, A ; Investigators, A ; Investigators, K ; Jakubowska, A ; Janni, W ; Jernström, H ; John, EM ; Johnson, N ; Jones, ME ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Marchand, LL ; Lindblom, A ; Lubiński, J ; Lux, MP ; Mannermaa, A ; Mavroudis, D ; Mulligan, AM ; Muranen, TA ; Nevanlinna, H ; Nevelsteen, I ; Neven, P ; Newman, WG ; Obi, N ; Offit, K ; Olshan, AF ; Park-Simon, T-W ; Patel, AV ; Peterlongo, P ; Phillips, K-A ; Plaseska-Karanfilska, D ; Polley, EC ; Presneau, N ; Pylkäs, K ; Rack, B ; Radice, P ; Rashid, MU ; Rhenius, V ; Robson, M ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmutzler, RK ; Schuetze, S ; Scott, C ; Shah, M ; Smichkoska, S ; Southey, MC ; Tapper, WJ ; Teras, LR ; Tollenaar, RAEM ; Tomczyk, K ; Tomlinson, I ; Troester, MA ; Vachon, CM ; van Veen, EM ; Wang, Q ; Wendt, C ; Wildiers, H ; Winqvist, R ; Ziogas, A ; Hall, P ; Pharoah, PDP ; Adank, MA ; Hollestelle, A ; Schmidt, MK ; Hooning, MJ ( 2023-02-13)
    Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).