Temple Univ/Fox Chase Cancer Ctr, Philadelphia, PA
John M. Kaczmar , Jessica Everett , Karen Ruth , Elena Martinez Stoffel , Jessica Stoll , Sonia Kupfer , Heather Hampel , Zsofia Kinga Stadler , Pragna Gaddam , Christina Rybak , Thomas Paul Slavin Jr., Jonathan P. Terdiman , Amie Blanco , Michael J. Hall
Background: Lynch syndrome (LS) is a well characterized hereditary cancer syndrome caused by mismatch repair (MMR) deficiency of epithelial tumors. Uncertainty remains as to whether several less common non-epithelial cancers such as sarcomas may also be associated with LS. We sought to describe the incidence and characteristics of sarcomas within a sample of LS families assembled through a multi-institutional collaboration. Methods: Participating sites (n = 7) queried their databases for molecularly proven and clinical LS families with sarcoma reported in a close relative (1st, 2nd, 3rd-deg). Information on the familial underlying MMR gene mutation (MLH1, MSH2, MSH6, PMS2, or EPCAM) was collected, as was age, sex, and tumor histology of all familial cancers from LS-sarcoma pedigrees (if available). Vague sarcoma diagnoses (“bone”) were considered possible, while a documented category/histology (“rhabdosarcoma”) was considered likely. Results: In total, from 958 LS families, 55 LS-sarcoma families (5.7%) contained 58 individuals with possible (n = 16) or likely (n = 42) sarcomas. Mean age of sarcoma diagnosis was 47.1 years (age range 4-87 years), with a 1:1 male to female ratio. Nearly two-thirds (62%, 36/58) of sarcomas were in MSH2+/EPCAM+ families, in contrast to the ~40% of all LS that are MSH2+. Other LS-sarcoma families were: MLH1+ (n = 12), MSH6+ (N = 3), PMS2+ (n = 3) and unknown (n = 4). Sarcoma histologies were diverse and included pleomorphic, synovial, myxofibroid, DFSP, liposarcoma, rhabdomyosarcoma, and osteosarcoma. Recurrent MSH2 mutations in presumed unrelated LS-sarcoma families included 2 known founder mutations del exon 1-6 and c.942+3A > T as well as c.1216C > T, c.2135insT and c.1906G > C. Other pedigree findings included: Muir-Torre variant LS in 14/38 (37%) evaluable families, 7 thyroid cancers (2 early-onset, 29 and 31 yrs), an adult retinoblastoma, and an MSI-H thymoma in a 55 year-old woman with 2 soft tissue sarcomas. Conclusions: From a large sample of nearly 1000 LS families, our findings suggest sarcomas may be a rare manifestation of LS, especially MSH2+ LS. More research of genotype-phenotype correlations in LS is needed.
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Abstract Disclosures
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