Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors

Abstract

Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.

Epidemiology of urothelial carcinoma

“…These abnormalities were also associated with urothelial neoplasms, particularly of the ureter and renal pelvis. 26 Patients at risk have an approximately 22-fold increased relative risk of developing UTUC. 27 The lifetime risk for urological cancer has been estimated to be approximately 8% by age 70 years, 26 and that is why some guidelines and experts recommend that all UTUC patients should be screened for HNPCC spectrum disease though a short interview, and should undergo DNA sequencing if they fulfill all criteria for HNPCC.…”

“…26 Patients at risk have an approximately 22-fold increased relative risk of developing UTUC. 27 The lifetime risk for urological cancer has been estimated to be approximately 8% by age 70 years, 26 and that is why some guidelines and experts recommend that all UTUC patients should be screened for HNPCC spectrum disease though a short interview, and should undergo DNA sequencing if they fulfill all criteria for HNPCC. 28 If DNA sequencing confirms the diagnosis of HNPCC syndrome, patients should undergo a clinical evaluation for other HNPCC-related cancers, a close follow up and familial genetic counseling.…”

Turcot Syndrome with Gliosarcoma: A rare variation of a Lynch Syndrome Phenotype

“…Using a national cohort of Lynch syndrome families from Finland, Gylling et al found that brain tumors were diagnosed at the average age of 38 years and that glioma was the most common histologic subtype [11]. Watson et al utilized a cohort of 6,176 members of 261 families to document that the risk of brain cancer in Lynch syndrome showed an overall lifetime risk of 2% [12].…”

Brain Tumors and the Lynch Syndrome

“…As a result of inactivation of both allelic copies, tumor tissues from LS patients typically show the absence of the respective MMR protein by immunohistochemical analysis (and occasionally, other MMR proteins as well in a defined pattern . This has been shown to apply to almost all colorectal carcinomas and extracolonic cancers of the LS spectrum, and brain tumors are no different (Gylling et al, 2008). Inactivation of a MMR gene is believed to initiate tumorigenesis through the failure of one or several essential functions that the MMR system is known to have, including repair of replication errors and a role in DNA damage signaling (Jiricny, 2006).…”