Association between tumor mutation burden (TMB) and MLH1, PMS2, MSH2, and MSH6 alterations in 395 microsatellite instability-high (MSI-High) gastrointestinal (GI) tumors

Salem, Mohamed E.; Grothey, A.; Goldberg, Richard M.; Xiu, Joanne; Korn, W. Michael; Shields, Anthony F.; Hwang, Jimmy J.; Philip, P. A.; Lenz, Heinz‐Josef; Marshall, John L.

doi:10.1093/annonc/mdy149.024

Cited by 4 publications

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“…However, this is so far not known for tumors arising in the context of Lynch syndrome. Apart from this, there is growing evidence of individual differences between patients, likely being dependent on the underlying MMR defect [28]. In line with this broad heterogeneity among MMR-D-related malignancies, we here show that MLH1 −/− tumors (I) are either hyper- or ultra-hypermutated, (II) have an entirely individual mutational profile and (III) harbor different mutational hotspots in affected genes.…”

Section: Discussionsupporting

confidence: 81%

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Gladbach

Wiegele

Hamed

et al. 2019

Cancers

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Mismatch repair deficient (MMR-D) tumors exemplify the prototypic hypermutator phenotype. Owing to the high mutation rates, plenty of neo-antigens are present on the tumor cells’ surface, ideally shared among different cancer types. The MLH1 knock out mouse represents a preclinical model that resembles features of the human MMR-D counterpart. While these mice develop neoplasias in a sequential twin-peaked manner (lymphomas > gastrointestinal tumors (GIT)) we aimed at identification of underlying molecular mechanisms. Using whole-genome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and describe the process of ongoing mutational events in tumor-derived cell cultures. The landscape of MLH1−/− tumors is heterogeneous with only a few shared mutations being detectable among different tumor entities (ARID1A and IDH2). With respect to coding microsatellite analysis of MMR-D-related target genes, partial overlap was detectable, yet recognizing shared antigens. The present study is the first reporting results of a comparison between spontaneously developing tumors in MMR-D driven tumorigenesis. Additionally to identifying ARID1A as potential causative mutation hotspot, this comprehensive characterization of the mutational landscape may be a good starting point to refine therapeutic concepts.

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Section: Discussionsupporting

confidence: 81%

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Gladbach

Wiegele

Hamed

et al. 2019

Cancers

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Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

Zhu

et al. 2020

Journal of the American College of Surgeons

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BACKGROUND:The frequency and significance of the germline variants in DNA damage repair genes still need to be elucidated in patients with sporadic pancreatic ductal adenocarcinoma (PDAC).Our purpose was to determine whether germline variants in DNA damage repair genes were associated with survival of patients with sporadic PDAC. STUDY DESIGN: We retrospectively identified 854 patients with sporadic PDAC with germline DNA sequenced in targeted 22 DNA damage repair genes by next-generation sequencing. Outcomes were compared in terms of clinicopathologic features, disease-free survival (DFS), and overall survival (OS). RESULTS: Nineteen patients had deleterious mutations; 103 had variant(s) of unknown significance (VUS). Germline DNA damage repair deleterious variant carriers had superior DFS (median, 19.1 months vs 11.9 months, p ¼ 0.012) and OS (median, 29.7 months vs 20.2 months, p ¼ 0.034), as compared with wild-type patients. Germline DNA damage repair VUS variant carriers also had superior DFS when compared with wild-type patients. In subgroup analysis, this improved survival was limited to patients receiving adjuvant chemotherapy, deleterious variant carriers vs wild-type patients DFS (median 36.3 months vs 13.1 months, p ¼ 0.006) and OS (median 43.7 months vs 24.3 months, p ¼ 0.045), VUS variant carriers vs wild-type patients DFS (16.5 months vs 13.1 months, p ¼ 0.007). CONCLUSIONS: Having a deleterious variant in a DNA damage repair gene is associated with improved survival after resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.

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Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

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28 29 Abbreviations: CMMR-D -constitutional mismatch repair deficiency, cMS -coding 30 microsatellite, MB -Megabase, MMR -mismatch repair, MMR-D -mismatch repair 31 deficiency, TMB -tumor mutational burden, GIT -gastrointestinal tumor, SNV -single 32 nucleotide variant, WES -whole exome sequencing 33 34 Keywords: Tumor mutational burden, exclusive/ shared mutations, predicted tumor antigens Mutations in MLH1 -/tumors 3 35Abstract 36 MLH1 knock out mice represent a preclinical model that resembles features of the human 37 counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a 38 sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at 39 identification of the underlying molecular mechanisms. Using whole-exome sequencing, we 40 focused on (I) shared and (II) mutually exclusive mutations and described the processes of 41 ongoing mutational events in tumor-derived cultures. 42 A heterogeneous genetic landscape was found, with few mutations shared among different 43 neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE 44 were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo 45 phenotype. Comparing the mutational profile of selected primary tumors and their 46 corresponding cell line upon in vitro culture revealed continuous increased numbers of 47 somatic gene mutations. The same was true for coding microsatellite mutations in selected 48 MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this 49 latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination 50 antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-51 protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease 52 ERCC5 (Excision Repair 5), involved in DNA excision repair. 53 Novel results of a comparison between spontaneously developing lymphomas and 54 gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition 55 to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive 56 characterization of the mutational signature is a starting point for immune-based approaches 57 to therapy. 58 59 Mutations in MLH1 -/tumors 4 60 Author Summary 61 This study describes the mutational spectrum of MLH1 -/--associated tumors, spontaneously 62 developing in mice. While these tumors arise at the bottom of the same germline mutation, 63 the clinical presentations as well as resulting molecular alterations are heterogeneous, and 64 thus likely being directly linked. Highly aggressive lymphomas, developing early in life are 65 ultra-hypermutated and harbor mutations in tumor suppressor genes SMAD4 and POLE. 66 Gastrointestinal tumors develop later in life and show different mutations. By performing in-67 depth whole exome sequencing analysis, we here identified for the first time a common 68 mutational hotspot. ARID1A constitutes a potentially causative mutati...

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Association between tumor mutation burden (TMB) and MLH1, PMS2, MSH2, and MSH6 alterations in 395 microsatellite instability-high (MSI-High) gastrointestinal (GI) tumors

Cited by 4 publications

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Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

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Association between tumor mutation burden (TMB) and MLH1, PMS2, MSH2, and MSH6 alterations in 395 microsatellite instability-high (MSI-High) gastrointestinal (GI) tumors

Cited by 4 publications

References 0 publications

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1−/− Mice

Association of Germline Variants in Human DNA Damage Repair Genes and Response to Adjuvant Chemotherapy in Resected Pancreatic Ductal Adenocarcinoma

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

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Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice