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• W1894388638 abstract "The case reported by Meyer and colleagues presents an interesting scenario in which a patient has multiple risk factors for the development of colorectal cancer (CRC) and, in fact, develops two adenocarcinomas, followed by a rectal lymphoma.1 Adding to the diagnostic dilemma, the patient may (or may not) have Lynch syndrome. Lynch syndrome is defined by the demonstration of a germline mutation in one of four DNA mismatch repair (MMR) genes2 and is associated with familial clusters of early-onset and, occasionally multiple, CRCs.3 However, there is no increase in lymphomas or hematologic malignancies in this setting.4 The patient had two early-onset CRCs and a strongly positive family history, but we do not have a confirmatory germline mutation to make the definitive diagnosis. The case is complicated by both chronic ulcerative colitis, which is a great risk factor for CRC,5 and immunosuppression after his liver transplant, which confers risk for an excess of cancers (at the very least, skin cancers, virally-driven cancers, and lymphomas). However, published studies do not consistently implicate an excess of CRCs in this situation.6 The question is whether a single unifying mechanism could account for all of the cancers in this patient. The answer is probably no, but two factors may be able to explain it.Lynch syndrome is an inherited disorder with germline mutations involving the DNA MMR system.7 Loss of function of any of the four key DNA MMR proteins (MSH2, MLH1, MSH6, or PMS2) reduces or abrogates the correction of errors in DNA replication and leads to microsatellite instability (MSI), which can be detected in the DNA of tumor tissues. The loss of DNA MMR activity creates MSI, which is a biomarker, and this “mutator phenotype” leads to the mutational activation of oncogenes or loss of expression of tumor suppressor genes, particularly when repetitive DNA sequences are involved.8 Thus, Lynch syndrome is associated with a cancer-prone phenotype. Lynch syndrome accounts for approximately 3% of all CRCs, and these patients are at risk for malignancies outside of the gastrointestinal tract.3,7 Approximately 15% of CRCs have MSI, but not all CRCs with MSI are due to Lynch syndrome. In fact, most (approximately 75–80%) of the CRCs with MSI (ie, 12% of the total) are due to the acquired methylation of the MLH1 gene, and this is almost always sporadic and not inherited.9 It would have been valuable to document a germline mutation in the MLH1 gene in this patient to confirm the presence of Lynch syndrome and that the MSI was not a consequence of acquired methylation of MLH1.Ulcerative colitis is a known risk factor for the development of colonic epithelial dysplasia and cancer. The precise underlying mechanism of this increased risk is not completely understood, but chronic inflammation is commonly associated with cancer in the affected tissue. It is known that cytokines, interleukins, and other mediators of inflammation locally induce oxidative stress and stimulate proliferation and repair.10,11 Making the situation even more problematic, experimental models have shown that oxidative stress is associated with the “relaxation” of DNA MMR12 and base excision repair (another type of DNA repair system),13 at the precise time that one would apparently require increased ability to repair DNA damage.This process takes time to occur. One can find MSI in the colonic epithelium of individuals with ulcerative colitis but not with acute infectious colitis.14 Although cancers arising in the setting of ulcerative colitis do not appear to have a single common molecular profile,15 there is an increase in MSI in colitis-associated cancers,16 and this does not appear to be a reflection of co-existing Lynch syndrome. Rather, the chronic inflammation is likely responsible for the methylation of the MLH1 gene in some cases, just as it occurs in the sporadic cases of CRC that have MSI.17As mentioned, there is no evidence that the increase in CRC in ulcerative colitis is related to unsuspected Lynch syndrome or to other variations in the DNA MMR genes.18 As the CRC did not express MLH1 or PMS2, the possibility of acquired methylation and loss of MLH1 remains. However, the patient’s family history also suggests Lynch syndrome, and the total loss of MLH1 and PMS2 is uncommon in colitis-associated CRCs. Thus, the best theory is that the CRCs represent Lynch syndrome-MLH1 type and that the colitis is coincidental. Having said this, the oxidative stress and other carcinogenic mechanisms associated with chronic inflammation may have contributed to the “second hit” or loss of the wild-type MLH1 gene, which is essential for the development of cancer in the setting of Lynch syndrome. To resolve this puzzle, it is possible to perform methylation analysis of the MLH1 gene in the tumor tissue, which disproves the diagnosis of Lynch syndrome. In addition, acquired methylation of MLH1 is often associated with a mutated BRAF gene,19 providing additional evidence that the problem with MLH1 was acquired and not inherited.20 These assays are currently available in research laboratories but will be more broadly available in pathology laboratories in the near future. Thus, it is possible to determine with reasonably high certainty whether this patient had Lynch syndrome. This would be of considerable importance to the patient’s family, as approximately 40% of familial clusters of CRC are not Lynch syndrome and fall into a category called “Familial Colorectal Cancer—Type X” that is not completely understood.21As far as fitting rectal lymphoma into the clinical picture, there is no significant excess of lymphomas in Lynch syndrome,4 as mentioned, though rectal lymphoma could presumably occur under the stressful conditions involved in this case. It would have been interesting to have performed an assay for MSI and immunohistochemistry for the DNA MMR proteins on the lymphoma tissue, as this could implicate Lynch syndrome in the genesis of the tumor. However, it is not possible to interpret a positive result with certainty, as lymphomas may occasionally show MSI.22 A negative result would tend to dissociate the lymphoma from the diagnosis of Lynch syndrome.Perhaps more germane to the complicating lymphoma was the involvement of 13 years of immunosuppression after liver transplantation. Lymphomas are known complications of long-term immunosuppression, where there is a spectrum of post-transplant lymphoproliferative disorders. Although approximately 25% of post-transplant lymphomas have extranodal involvement, it is interesting that the lymphoma arose in the rectal remnant that was involved with colitis and chronic inflammation. This inflammatory environment no doubt contributed to the development of this lymphoma.In conclusion, the patient discussed by Meyer and associates presents an interesting scenario in the milieu of multiple risk factors for colorectal and hematologic malignancies. The patient’s inflammatory bowel disease, primary sclerosing cholangitis, and immunosuppression were all risk factors. Another important consideration was the possibility of Lynch syndrome. In the end, this patient’s clinical course was complicated by multiple malignancies. The question of whether to screen is frequently considered in patients such as this one. Fortunately, this clinical situation is not a common one (which is why there are no formal guidelines regarding CRC screening in a patient with such a unique set of risk factors). An aggressive screening regimen did not prevent the development of cancers in this patient. As more is learned regarding the interplay of host surveillance, inflammation, and genetic variables in tumorigenesis, and as we apply more accurate biomarkers to these problems, we are certain to make progress." @default.
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• W1894388638 title "Post-Transplant Rectal Lymphoma After Subtotal Colectomy for Lynch Syndrome–Associated Colorectal Adenocarcinoma." @default.
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