Dataset Information

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

ABSTRACT:

Background

Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics.

Methods

We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors.

Results

In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5).

Conclusions

In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.

SUBMITTER: Elze L

PROVIDER: S-EPMC10323896 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

Elze Lisa L van der Post Rachel S RS Vos Janet R JR Mensenkamp Arjen R AR de Hullu Mirjam S C MSC Nagtegaal Iris D ID Hoogerbrugge Nicoline N de Voer Richarda M RM Ligtenberg Marjolijn J L MJL

Journal of the National Cancer Institute 20230701 7

<h4>Background</h4>Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics.<h4>Methods</h4>We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lync ...[more]

PMID: 37018159

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Project description:BackgroundLynch syndrome (LS) is one of the most common hereditary cancer syndromes worldwide. Dominantly inherited mutation in one of four DNA mismatch repair genes combined with somatic events leads to mismatch repair deficiency and microsatellite instability (MSI) in tumours. Due to a high lifetime risk of cancer, regular surveillance plays a key role in cancer prevention; yet the observation of frequent interval cancers points to insufficient cancer prevention by colonoscopy-based methods alone. This study aimed to identify precancerous functional changes in colonic mucosa that could facilitate the monitoring and prevention of cancer development in LS.MethodsThe study material comprised colon biopsy specimens (n = 71) collected during colonoscopy examinations from LS carriers (tumour-free, or diagnosed with adenoma, or diagnosed with carcinoma) and a control group, which included sporadic cases without LS or neoplasia. The majority (80%) of LS carriers had an inherited genetic MLH1 mutation. The remaining 20% included MSH2 mutation carriers (13%) and MSH6 mutation carriers (7%). The transcriptomes were first analysed with RNA-sequencing and followed up with Gorilla Ontology analysis and Reactome Knowledgebase and Ingenuity Pathway Analyses to detect functional changes that might be associated with the initiation of the neoplastic process in LS individuals.FindingsWith pathway and gene ontology analyses combined with measurement of mitotic perimeters from colonic mucosa and tumours, we found an increased tendency to chromosomal instability (CIN), already present in macroscopically normal LS mucosa. Our results suggest that CIN is an earlier aberration than MSI and may be the initial cancer driving aberration, whereas MSI accelerates tumour formation. Furthermore, our results suggest that MLH1 deficiency plays a significant role in the development of CIN.InterpretationThe results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS.FundingThis work was supported by grants from the Jane and Aatos Erkko Foundation, the Academy of Finland (330606 and 331284), Cancer Foundation Finland sr, and the Sigrid Jusélius Foundation. Open access is funded by Helsinki University Library.

Project description:PurposeMicrosatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.MethodsMSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.ResultsAmong 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.ConclusionMSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

Dataset Information

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

Background

Methods

Results

Conclusions

Publications

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

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