MLH3 mutation

P=N/A, N=880, Not yet recruiting, Assistance Publique - Hôpitaux de Paris | Trial completion date: Nov 2027 --> Jul 2029 | Trial primary completion date: Nov 2027 --> Jul 2029

P1/2, N=58, Completed, Asan Medical Center | Active, not recruiting --> Completed

The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.

For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%)...Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions.

Our study revealed heterogeneity of NENs, and identified novel prognostic signatures and potential therapeutic targets, which directing improvements of clinical management for NEN patients in the foreseeable future.

Because both the ATM and MRE11 genes, which as act as players in the MNR (MRE11/NBS1 (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences.

P1/2, N=58, Active, not recruiting, Asan Medical Center | Unknown status --> Active, not recruiting | Trial completion date: Jun 2021 --> Jun 2023 | Trial primary completion date: Jun 2021 --> Jun 2023

Analysis of 180,000 tumors revealed a high concordance of IHC-MMR/NGS-MSI with a rate of 99.7%. In 20% of MMRp/MSI-H cases, interpretation of IHC lead to misdiagnosis that the NGS-MSI would have avoided. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd.

Here we report from >28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy.

P=N/A, N=880, Not yet recruiting, Assistance Publique - Hôpitaux de Paris

This study examined the RIM in a cohort of patients having received similar doses of radiation for their childhood cancer. There is increased risk of radiation-induced meningioma in survivors of non-CNS cancers given ≥ 2000 cGy during childhood. To date, our findings are consistent with previously described primary and RIM mutations.

Also, the expression of MLH3 decreased significantly in patients with breast cancer grades of II and III. In conclusion, MLH3 can be used as a susceptibility gene especially in grades II and III of breast cancer.

P=N/A, N=100, Not yet recruiting, Fujian Cancer Hospital

Responses to immune checkpoint inhibitors in mismatch repair-deficient/microsatellite instability-high tumours of other locations have shown promising results, and with the extended approval of the PD-1 receptor inhibitor pembrolizumab by the Food and Drug Administration, also anaplastic thyroid cancer (ATC) requires analysis for microsatellite instability (MSI) status...There are insufficient and heterogenous data concerning the predictive or prognostic value of mismatch repair-deficient/microsatellite instability status. Tumour molecular profiling is fundamental in ATC for predictive, prognostic, as well as therapeutic reasons, and analysis of MSI status is strongly suggested because a small subgroup show the MSI signature and might profit from recently approved targeted therapies.

In two independent genomic datasets from TCGA and Tianjin cohorts, low risk scores were associated with higher tumor mutation loads and improved outcome in patients with gastric adenocarcinoma. This finding may have implications for prognostic prediction and therapeutic guidance for gastric adenocarcinoma.

Somatic MMR mutations tend to increase TMB. Adequate investigation should be made to determine immunotherapy efficacy in these patients.

Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ, XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2, SETD1B) or other cellular pathways: LRRK2 (2 cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

A comprehensive molecular analysis of the primary tumor guided by histologic analysis may help to better stratify patients for precision medicine approaches. Given the association between the molecular and the histologic heterogeneity, the selection of tumor samples for molecular analysis should be based on meticulous histologic evaluation of the entire tumor.

This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed.

No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants.

Our study proved heterogenous pattern of clonal evolution in gliomas which is characterized by acquisition of new genomic aberrations and leads to high genome instability. We proved, that recurrences are genetically/epigenetically different from their primaries and may arise from one major tumor clone or by one or more subclones presented within primary tumors.Supported by RVO-VFN64165

This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed.

Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.

Until very recently, FDA approved the first molecularly targeted therapy with the PARP inhibitor Olaparib for pancreatic cancer patients with germline mutations on BRCA1/2, two types of homologous recombination (HR)/DNA damage repair (DDR) genes...The BRCA1/2 germline mutations were found at low levels in our cohort (0.8%) compared to the American cohorts ( 2.4~2.7%), Furthermore, the whole DDR mutations exhibited highest proportion [10.5% (27/256) from our study, compared with 7.3% (21/289) from Yurgelun, and 5.4% (10/185) from TCGA, respectively].CONCLUSIONIn conclusion,our results characterized the germline mutation landscape of DDRs in the largest oriental cohort of pancreatic cancer to date, and first discovered two novel germline mutations in pancreatic cancer. Most importantly, nearly 10% of PDAC patients in this study were found to harbor germline DDR mutations, which may benefit more patients with an effective therapeutic synergy for PARP and PD-1 inhibitors in clinical practice.

Legal entity responsible for the study The authors. Funding Has not received any funding.

Our study retrospectively analyzed germline mutation profile of prostate cancer in Chinese population. The frequency of HSD3B1 (1245C) allele varies across ethnic populations in spite of the similar DNA repair gene mutations rates. Considering the gene list should be tested based on clinical/familial scenarios from the Philadelphia Prostate Cancer Consensus Conference, a prevalence of certain mutations, G84E mutation in HOXB13 was unnecessary for genetic testing in Chinese population.

EEC G3 harbored the most MMR mutations among EC. EEC G3 and USC could be more considered to screen MMR mutation due to more MMR mutations occurred in EEC G3 and USC than did among EEC G2 and EEC G1. Besides MLH1, MSH2, MSH6, PMS2 and EPCAM mutation, MLH3, MSH3, PMS1 mutation could be screened in patients with newly diagnosed endometrial carcinoma.

2.9% patients were identified as MSI-H in Chinese prostate patients. MSI-H was associated with higher TMB, SNVs and Indels. Targeted next-generation sequencing is a practical tool for prostate cancer genotyping and treatment decision-making.

4.5% of patients carrying germline variants may be linked to increased susceptibility to lung cancer. The susceptibility is mainly reflected in family history and morbidity risk without significant influence on aberrant pathways. Research Funding: the Special Funds for Strategic Emerging Industry Development of Shenzhen (grant number 20170922151538732), the Science and Technology Project of Shenzhen (grant number JSGG20180703164202084)