Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome

Abstract

Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

“…They also found that it did not segregate with disease in two families, and noted that these observations together are consistent with a low-penetrance Lynch syndrome mutation. Gargiulo et al 56 came to the same conclusion after finding K618A in an unaffected branch of a Lynch syndrome family. Our observations confirm these findings and also greatly extend them.…”

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy

“…Pedigree review was conducted for 225 PC patients enrolled between February 1999 and February 2011 within the framework of an ongoing case-control study on the genetics of PC [21][22][23]. The study was approved by the Ethics Committees of the three participating hospitals (San Martino Hospital, Galliera Hospital and National Cancer Institute).…”

Familial aggregation of malignant tumors in patients with pancreatic cancer: Findings from the Ragusa Cancer Registry (Sicily)

“…Finally, Panel C shows simple familial aggregation, with several malignancies in the family, but no apparent verticality for pancreatic cancer (see Figures 2, 3). The most frequently reported cancers in the relatives of probands were those of the breast (43 cases, 16.5% of the total), central nervous system (CNS) (23,8.8%), stomach (22,8.4%), and colon-rectum (22, 8.4%). Interestingly, a large fraction of these cancers (90 out of 261, 34.5%) occurred before the age of 56 years (see Table 2).…”

“…In 1990, Lynch et al [22] described the main features of 18 families with a strong aggregation of pancreatic cancer among relatives, estimating that some 6% of pancreatic cancer patients had a family history of the disease and that this phenomenon could be attributed to an as yet undefined genetic predisposition. More recently, Gargiulo et al [23] found that 19 of the 135 pancreatic cancer patients in their study sample could be classified as having suspected Lynch syndrome, and four of these 19 patients had constitutional alterations in the MLH1 or MSH2 genes. Tersmette et al [24] found a high risk of pancreatic cancer among individuals who have at least 3 first-degree relatives with pancreatic neoplasms.…”