Lynch syndrome (OMIM #s 120435, 609310) is an autosomal dominant cancer predisposition syndrome that underlies about 3–5% of all colorectal cancers.^1-5 It is caused by germline mutations in one of several DNA mismatch repair genes, including MSH2, MLH1, MSH6, and PMS2. The genetic heterogeneity has made diagnostic testing a challenge, such that use of tumor assessment of either DNA mismatch repair deficiency (microsatellite instability) and/or expression of the four DNA mismatch repair gene products has been widely used to screen suspected cases. The Bethesda guidelines⁶ put forth recommendations based upon expert opinion for when tumor testing should be considered. Under that report, the cancers listed as Lynch Syndrome-associated included colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel. Although pancreatic cancer is included in this list, risk usually appears to be only minimally increased, relative to the general population.

We have been following a family with a novel MSH2 missense alteration in which pancreatic cancer has been more commonly observed than colon or endometrial cancer (Figure 1). The ancestry is Northern European. None of the affected individuals smoked cigarettes nor had known exposure to unusual environmental agents. There is no family history of melanoma, early onset breast cancer, ovarian cancer, or pancreatitis. Table 1 lists the cancers of all relevant family members, and, where available, the results of tumor immunohistochemical expression of the DNA mismatch repair genes. All testing was done at Mayo Clinic using standard techniques.^7–9 The MSH2 germline change, identified by sequencing, is in exon 6, c.1046C>T, (CCT>CTT), p.Pro349Leu, hereafter called P349L. This variant co-segregates with the development of pancreatic cancer and with the loss of MSH2 expression in tumor tissue in this family. The details of this family have not previously been published; however one aspect of this family’s laboratory results was included in a prior publication that reported on use of BRAF screening as a strategy to simplify HNPCC genetic testing.^{10, 11} No BRAF V600E somatic mutation was found in the MSI-high tumor tested in this family, consistent with this being a Lynch Syndrome family. The kindred is enrolled in an ongoing familial pancreatic cancer registry and an affected individual was studied and found to be negative for CFTR and CDKN2A mutations.

Available data suggest that, in general, penetrance for pancreatic cancer in Lynch Syndrome is low. Prior to discovery of the genetic basis of the Lynch Syndrome, Watson and Lynch (1993) studied 1,424 at-risk persons from 23 large families (with 287 colorectal cancers) who were suspected of having this disorder.²² Six pancreatic cancers were recorded, compared with 4.1 expected, which was not statistically significantly different. In l999, Aarnio et al. had studied 360 gene carriers of 50 families with gene mutations (94% in MLH1 and 6% in MSH2), and found 3 pancreatic cancers, giving a Standardized Incidence Ratio of 4.5, but with a 95% CI of 1.0–14.²³ In 2008, in a study that assessed extracolonic cancer risk among 6,041 members of 261 families with documented mutations in MLH1 (60%) or MSH2 (40%), cancers of the biliary tract, liver and pancreas combined accounted for 1.09% of the cancers in this study, giving a hazard ratio of 1.869 and a cumulative incidence of 4.1% to age 70 years.²⁴ Most recently, risk of pancreatic cancer alone was addressed in 6,342 individuals from 147 families with MMR mutations (37.4% in MLH1, 55.1% in MSH2, and 7.55% in MSH6). A cumulative risk of pancreatic cancer was calculated as 1.31% (95% CI=0.31–2.32%) to age 50, and 3.68% (95% CI=1.45–5.88%) to age 70, which is an 8.6-fold (95% CI=4.7–15.7%) increase compared with the general population.²⁵ In summary, we present a family in which a novel P349L missense substitution in MSH2 that co-segregates with disease in a Lynch Syndrome family appears particularly to be associated with a high risk for pancreatic cancer. All three cancer affected individuals carry the MSH2 P349L missense substitution, and there is loss of expression of MSH2/MSH6 in each of their pancreatic tumors. Together with in silico predictions, these data provide support that this alteration is the causative mutation. It would be of interest to learn of other families with the same missense alteration to determine if predisposition to pancreatic cancer is consistently associated with this MSH2 change.