Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome

Paula, André Escremim de; Galvão, Henrique de Campos Reis; Bonatelli, Murilo; Sabato, Cristina S; Fernandes, Gabriela; Berardinelli, Gustavo Nóriz; Andrade, Carlos; Neto, Maximiliano Cadamuro; Romagnolo, Luis Gustavo Capochim; Campacci, Natália; Scapulatempo‐Neto, Cristovam; Reis, Rui Manuel; Palmero, Edenir Inêz

doi:10.1016/j.cancergen.2021.02.003

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…Several studies do not include MLH1 -methylated cases in LLS germline investigations [ 8 , 14 ]. Yet, the presence of tumors with MLH1 methylation does not exclude the presence of germline variants in LS patients [ 9 ]; we identified the presence of pathogenic variants in 50% of our MLH1 -methylated cases. Interestingly, there were two pathogenic variants not previously reported in the literature, which were identified in MLH1 -methylated cases from our study.…”

Section: Discussionmentioning

confidence: 98%

“…Patients were included after signing an informed consent form, and the study was approved by the Barretos Cancer Hospital Institutional Review Board (protocol CAAE: 56164716.9.0000.5437). The patient selection followed the Lynch syndrome strategy as previously reported [ 9 ]. Briefly, samples from patients meeting the Amsterdam or Bethesda criteria underwent immunohistochemistry (IHC) for the four MMR-related proteins (MLH1, PMS2, MSH2 and MSH6) and microsatellite instability (MSI) analysis.…”

Section: Methodsmentioning

confidence: 99%

“…A previous study from our group [ 9 ] evaluated 323 probands with a family history suggestive of LS. Among those, 134 tumors were MMR-deficient.…”

Section: Introductionmentioning

confidence: 99%

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Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

Santos

Andrade

Garcia

et al. 2022

Cancers

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Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as MUTYH and ATM. Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene POLN and other cancer-related genes such as PPARG, CTC1, DCC and ALPK1. Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

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Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

Santos

Andrade

Garcia

et al. 2022

Cancers

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“…Thirty-nine patients from 34 families identified at the Oncogenetics Department of Barretos Cancer Hospital 46 were included in the study after signing the informed consent. All participants were negative for LS, which diagnostic is composed by immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 proteins; BRAF (V600E) sequencing and microsatellite instability (MSI) evaluation by fragment analysis 47 . Besides, gene panel sequencing by NGS is performed for all patients with High MSI or altered IHC.…”

Section: Methodsmentioning

confidence: 99%

New insights on familial colorectal cancer type X syndrome

Garcia

Andrade

Galvão

et al. 2022

Sci Rep

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Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, although displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability. Besides, its genetic etiology remains to be elucidated. In this study we performed germline exome sequencing of 39 cancer-affected patients from 34 families at risk for FCCTX. Variant classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic/likely pathogenic variants were identified in 17.65% of the families. Rare and potentially pathogenic alterations were identified in known hereditary cancer genes (CHEK2), in putative FCCTX candidate genes (OGG1 and FAN1) and in other cancer-related genes such as ATR, ASXL1, PARK2, SLX4 and TREX1. This study provides novel important clues that can contribute to the understanding of FCCTX genetic basis.

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“…The median follow-up of our cases was 62.0 months. During the inclusion period, patients diagnosed with Lynch Syndrome were excluded [21]. Clinicopathological and treatment data was recently reported [18].…”

Section: Methods Participantsmentioning

confidence: 99%

Association of microsatellite instability (MSI) status with the 5-year outcome and genetic ancestry in a large Brazilian cohort of colorectal cancer

et al. 2022

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Colorectal cancer (CRC) has a high incidence and mortality worldwide. Microsatellite instability (MSI) is crucial in CRC, with distinct molecular and clinicopathological features in patients. Nowadays, it is a predictive marker for immunotherapy. We proposed to evaluate the 5-year outcome of MSI status in 1002 Brazilian CRC, and associate it with genetic ancestry, molecular and clinicopathological features. MSI evaluation was performed using molecular markers. MSI+ tumors were analyzed for alterations in 23 MSI-targeted genes. Genetic ancestry was evaluated using an Ancestry-Informative markers panel. MSI status was analyzed in relation to CRC specific survival and other clinical and genetic variables. MSI+ status was observed in 10.5% of cases. MSI+ status was significantly associated with the anatomic site right colon, mucinous histological type, clinical stage II, histological grade III/ undifferentiated, no recurrence of disease, and live cases without cancer. No association of MSI status with genetic ancestry components was observed. MSI-targeted genes analyses showed the most frequently altered genes: ATM, EGFR, MRE11, ROCK1, and TGFBRII. There was a statistically significant difference in cancer-specific survival between cases according to MSI status. This study constitutes the most comprehensive analyses of the MSI impact on the Brazilian CRC. MSI+ frequency in Brazilian CRC agreed with the literature and was associated with several clinicopathological features related with less aggressive tumors, independently of their genetic ancestry.

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Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome

Cited by 8 publications

References 33 publications

Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome

New insights on familial colorectal cancer type X syndrome

Association of microsatellite instability (MSI) status with the 5-year outcome and genetic ancestry in a large Brazilian cohort of colorectal cancer

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