Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the MLH1 UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients.

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Faculty Opinions recommendation of Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718206849.793492961 ◽

2014 ◽

Author(s):

Randall Brand

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Somatic Mutations ◽

Mismatch Repair Deficiency ◽

Repair Deficiency

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Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening

Gynecologic Oncology ◽

10.1016/j.ygyno.2020.09.039 ◽

2020 ◽

Vol 159 (3) ◽

pp. 712-720

Author(s):

Caitlin Carr ◽

Jessica Son ◽

Meng Yao ◽

Anju Priyadarshini ◽

Jessica Marquard ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Cancer Patients ◽

Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Clinicopathologic Characteristics ◽

Repair Deficiency

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Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001927 ◽

2020 ◽

Vol 30 (12) ◽

pp. 1951-1958

Author(s):

Soyoun Rachel Kim ◽

Alicia Tone ◽

Raymond Kim ◽

Matthew Cesari ◽

Blaise Clarke ◽

...

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Ovarian Tumor ◽

Tumor Site ◽

Mismatch Repair Deficiency ◽

Ovarian Cancers ◽

Repair Deficiency ◽

Endometrial Tumor ◽

Germline Testing

ObjectivesFor synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.Methods30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.ResultsOf 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.ConclusionsThere was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

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Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106303 ◽

2019 ◽

Vol 57 (7) ◽

pp. 505-508 ◽

Cited By ~ 1

Author(s):

Helen Toledano ◽

Naama Orenstein ◽

Efrat Sofrin ◽

Noa Ruhrman-Shahar ◽

Gil Amarilyo ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Mismatch Repair ◽

Lupus Erythematosus ◽

Neurofibromatosis Type ◽

Diagnostic Feature ◽

Mismatch Repair Deficiency ◽

Systemic Lupus ◽

Repair Deficiency ◽

Biallelic Mutations ◽

Constitutional Mismatch Repair Deficiency

Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in MSH6. Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features

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