Germline <i><scp>MLH</scp>1, <scp>MSH</scp>2</i> and <i><scp>MSH</scp>6</i> variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome

Schneider, Natália; Pastor, Tatiane; Paula, André Escremim de; Achatz, Maria Isabel; Santos, Ândrea Ribeiro dos; Vianna, Fernanda Sales Luiz; Rosset, Clévia; Pinheiro, Manuela; Ashton‐Prolla, Patrícia; Moreira, Miguel Ângelo Martins; Palmero, Edenir Inêz; Silva, Patrícia Santos; Koehler‐Santos, Patrícia; Cossio, Silvia Liliana; Netto, Cristina; Silva, Gustavo Stumpf da; Vargas, Fernando; Lima, Maria Angélica de; Scapulatempo‐Neto, Cristovam; Reis, Rui Manuel; Carvalho, André Lopes; Pinto, Carla; Teixeira, Manuel Rui; Viana, Danilo Vilela; Rossi, Benedito Mauro; Oliveira, Júnea Cáris de; Galvão, Henrique C R; Assumpção, Paulo Pimentel de; Ishak, Geraldo; Júnior, Sérgio Lima

doi:10.1002/cam4.1316

Cited by 21 publications

(16 citation statements)

References 56 publications

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“…Gastric cancer occurrence has a frequency of 1–6% in individuals with a Lynch syndrome-associated mutation, and this risk increases by 9% for those that present germline MSH2 mutations [ 43 , 44 ]. In this study, a mutation in this gene was identified in a gastric cancer patient (c.388_389delCA) – until now, this variant had been reported only in Brazilian Lynch syndrome patients [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 96%

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

et al. 2021

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Background Next generation sequencing (NGS) has been a handy tool in clinical practice, mainly due to its efficiency and cost-effectiveness. It has been widely used in genetic diagnosis of several inherited diseases, and, in clinical oncology, it may enhance the discovery of new susceptibility genes and enable individualized care of cancer patients. In this context, we explored a pan-cancer panel in the investigation of germline variants in Brazilian patients presenting clinical criteria for hereditary cancer syndromes or familial history. Methods Seventy-one individuals diagnosed or with familial history of hereditary cancer syndromes were submitted to custom pan-cancer panel including 16 high and moderate penetrance genes previously associated with hereditary cancer syndromes (APC, BRCA1, BRCA2, CDH1, CDKN2A, CHEK2, MSH2, MSH6, MUTYH, PTEN, RB1, RET, TP53, VHL, XPA and XPC). All pathogenic variants were validated by Sanger sequencing. Results We identified a total of eight pathogenic variants among 12 of 71 individuals (16.9%). Among the mutation-positive subjects, 50% were diagnosed with breast cancer and had mutations in BRCA1, CDH1 and MUTYH. Notably, 33.3% were individuals diagnosed with polyposis or who had family cases and harbored pathogenic mutations in APC and MUTYH. The remaining individuals (16.7%) were gastric cancer patients with pathogenic variants in CDH1 and MSH2. Overall, 54 (76.05%) individuals presented at least one variant uncertain significance (VUS), totalizing 81 VUS. Of these, seven were predicted to have disease-causing potential. Conclusion Overall, analysis of all these genes in NGS-panel allowed the identification not only of pathogenic variants related to hereditary cancer syndromes but also of some VUS that need further clinical and molecular investigations. The results obtained in this study had a significant impact on patients and their relatives since it allowed genetic counselling and personalized management decisions.

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Section: Discussionmentioning

confidence: 96%

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

et al. 2021

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“…However, one proband had VUS in DNA repair system genes ( MSH2 c.2078G > A (p.Cys693Tyr) and c.2072T > C (p.Ile691Thr), TSC1 c.1460C > G (p.Ser487Cys) and ERCC2c .691G > A (p.Val231Met) which were considered as potentially pathogenic by two predictive analyzes in silico . Missense variant c.2078G > A in mismatch repair gene MSH2 was previously described in Brazilian patients with LS (49, 50). Another mutation MSH2 c.2072T > C/p.Ile691Thr was also reported in individuals with LS from Swiss families and in individuals from Utah and California (51, 52).…”

Section: Discussionmentioning

confidence: 98%

Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer

et al. 2019

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Background: Colorectal cancer (CRC) incidence is rising worldwide, as well as in the Republic of Kazakhstan, while its occurrence is also increasing in the younger population. Hereditary forms associated with the development of colon and rectal cancer and early-onset CRC have never been studied in the population of Kazakhstan. The aim of this research was to investigate the spectrum of CRC-related gene mutations to determine which mutations cause early onset of CRC in the Kazakhstan population. Methods: The study included 125 unrelated patients from Kazakhstan (range 17–50 years in age) with early onset CRC. Genomic DNA was obtained from peripheral blood of the patients. Next-generation sequencing was performed using the TruSightCancer Kit on the MiSeq platform. The Studio Variant was used to annotate and interpret genetic variants. Results: Bioinformatics analysis of Next-generation sequencing data revealed 11,152 variants from 85 genes, of them, 3,790 missense, 6,254 synonymous variants, 44 3′UTR variants, 10 frameshift variants, five stop-gain variants, four in-frame deletions, two splice donors, one splice acceptor variant, and 1,042 intron or non-coding variants. APC, BRCA2/1, ALK, BRIP1, EGFR, FANCA, FANCD2, FANCI, HNF1A, MEN1, NSD1, PMS2, RECQL4, RET, SLX4, WRN , and XPC genes mutated most often. According to the ACMG guidelines and LOVD/ClinVar databases, 24 variants were pathogenic (10 frameshifts, five missenses, five stop-gain, one in-frame deletion, and three splice-site mutations), and 289 were VUS with population frequency <1%, 131 of them were attributed as deleterious. In the study, 50% of all pathogenic mutations found in Kazakhstani patients with early CRC onset were identified in the subgroups with a family history of CRC and primary multiple tumors. In APC , pathogenic mutations were most often (21%). Conclusion: Pathogenic and likely pathogenic mutations were found in 20 (16%) out of 125 patients. Eight novel pathogenic mutations detected in FANCI, APC, BMPR1, ATM , and DICER1 genes have not been reported in previous literature. Given the high frequency and wide spectrum of mutations, NGS analysis must be carried out in families with a history of CRC/CRC-related cancers with the purpose to identify cause-effective mutations, clarify the clinical diagnosis, and prevent the development of the disease in other family members.

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“…The question remains as to whether the MLH1 K618E and MLH1 K618T exist at all in populations, or at very low frequencies (approximately 100-fold lower based on the numbers cited above). Notably, the MLH1 K618E and MLH1 K618T alleles are listed in the Clinvar database, and reported in patient samples [59][60][61] . It is unclear if the three alleles arose independently, or if they were derived from one another.…”

Section: Discussionmentioning

confidence: 99%

MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Singh

Fragoza

Blengini

et al. 2021

Preprint

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Most spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genes MLH1 and MLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine if MLH1/3 variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nine MLH1 and MLH3 variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

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Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome

Cited by 21 publications

References 56 publications

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

Mutation Spectrum of Cancer-Associated Genes in Patients With Early Onset of Colorectal Cancer

MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging

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