Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants

Abstract

<jats:p>Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir–Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options.</jats:p>

Mismatch repair deficiency is rare in bone and soft tissue tumors

“…Undifferentiated pleomorphic/unclassifiable sarcoma accounted for eight cases and in one cases the subtype was not specified. 4 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 While most studies referred to case reports or case series, Doyle and colleagues investigated the frequency of MMR deficiency in a cohort of 279 cases and identified 6 MMR deficient cases (2%). 26 In all these studies, seventeen patients had a germline mutation in one of the mismatch repair genes (Lynch syndrome n = 13; Muir‐Torre syndrome n = 2; Constitutional Mismatch Repair Deficiency n = 2).…”

An observational study of synchronous/metachronous tumours in microsatellite unstable/mismatch repair deficient endometrial carcinomas

“…Sporadic sarcomas are rarely associated with microsatellite instability. However, a Brazilian study recently indicated that sarcomas, although rare, are linked to the Lynch syndrome spectrum of tumours [28,29]. An increased lifetime incidence is reported; but the exact risk for sarcoma development has not been fully elucidated [28].…”

The Study of Cancer Susceptibility Genes

“…It is well established that defects in DNA mismatch repair (Lynch syndrome) predispose to colon and other cancers. The new study found that the condition can also lie in the etiology of sarcomas [ 7 ]. Fanconi anemia is connected to the defects of machinery dealing with the aberrant replication of damaged DNA with inter-strand DNA crosslinks.…”

“…in the etiology of sarcomas [7]. Fanconi anemia is connected to the defects of machinery dealing with the aberrant replication of damaged DNA with inter-strand DNA crosslinks.…”