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Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)

Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant...

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Autores principales: Han, Quanli, Liu, Si, Cui, Zhi, Wang, Qi, Ma, Tonghui, Jiang, Liwen, Li, Xiaomo, Dai, Guanghai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804326/
https://www.ncbi.nlm.nih.gov/pubmed/35116055
http://dx.doi.org/10.3389/fgene.2021.799807
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author Han, Quanli
Liu, Si
Cui, Zhi
Wang, Qi
Ma, Tonghui
Jiang, Liwen
Li, Xiaomo
Dai, Guanghai
author_facet Han, Quanli
Liu, Si
Cui, Zhi
Wang, Qi
Ma, Tonghui
Jiang, Liwen
Li, Xiaomo
Dai, Guanghai
author_sort Han, Quanli
collection PubMed
description Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months.
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spelling pubmed-88043262022-02-02 Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A) Han, Quanli Liu, Si Cui, Zhi Wang, Qi Ma, Tonghui Jiang, Liwen Li, Xiaomo Dai, Guanghai Front Genet Genetics Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months. Frontiers Media S.A. 2022-01-18 /pmc/articles/PMC8804326/ /pubmed/35116055 http://dx.doi.org/10.3389/fgene.2021.799807 Text en Copyright © 2022 Han, Liu, Cui, Wang, Ma, Jiang, Li and Dai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Han, Quanli
Liu, Si
Cui, Zhi
Wang, Qi
Ma, Tonghui
Jiang, Liwen
Li, Xiaomo
Dai, Guanghai
Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title_full Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title_fullStr Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title_full_unstemmed Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title_short Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
title_sort case report and literature review: diagnosis, tailored genetic counseling and cancer prevention for a locally advanced dmmr/msi-h/tmb-h lung cancer patient with concurrent lynch syndrome mediated by a rare pms2 splicing variant (c.1144+1g>a)
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804326/
https://www.ncbi.nlm.nih.gov/pubmed/35116055
http://dx.doi.org/10.3389/fgene.2021.799807
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