P-242 Germline mutations identified in Colombian patients with Lynch syndrome

AbstractPatients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

Download Full-text

Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome

JAMA ◽

10.1001/jama.2011.743 ◽

2011 ◽

Vol 305 (22) ◽

pp. 2304 ◽

Cited By ~ 583

Author(s):

Valérie Bonadona

Keyword(s):

Lynch Syndrome ◽

Germline Mutations ◽

Cancer Risks

Download Full-text

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome

Familial Cancer ◽

10.1007/s10689-009-9258-4 ◽

2009 ◽

Vol 8 (4) ◽

pp. 421-429 ◽

Cited By ~ 12

Author(s):

Gašper Berginc ◽

Matej Bračko ◽

Metka Ravnik-Glavač ◽

Damjan Glavač

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Cancer Patients ◽

Germline Mutations ◽

Specific Detection ◽

Detection Strategy ◽

Colorectal Cancer Patients

Download Full-text

Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome

Yearbook of Obstetrics Gynecology and Women s Health ◽

10.1016/s1090-798x(08)70250-9 ◽

2007 ◽

Vol 2007 ◽

pp. 356-357

Author(s):

J.S. Dungan

Keyword(s):

Cancer Risk ◽

Lynch Syndrome ◽

Germline Mutations

Download Full-text

Nine novel pathogenic germline mutations inMLH1,MSH2,MSH6andPMS2in families with Lynch syndrome

Acta Oncologica ◽

10.1080/02841860701230217 ◽

2007 ◽

Vol 46 (6) ◽

pp. 763-769 ◽

Cited By ~ 9

Author(s):

Nils Rahner ◽

Nicolaus Friedrichs ◽

Maria Wehner ◽

Verena Steinke ◽

Stefan Aretz ◽

...

Keyword(s):

Lynch Syndrome ◽

Germline Mutations

Download Full-text

Mismatch Repair Genes and EPCAM germline mutations in patients with gastric or colorectal cancer with suspected of Lynch syndrome.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e13623 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e13623-e13623 ◽

Cited By ~ 1

Author(s):

Nora Manoukian Forones ◽

Fernanda Tereza Lima ◽

Renan Paulo Martin ◽

Leonardo Martins ◽

Patricia Valera Lima Teixeira ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Germline Mutations ◽

Mismatch Repair Genes ◽

Repair Genes

Download Full-text

A pan-cancer analysis of microsatellite instability as a predictor of Lynch syndrome in Chinese population.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1574 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1574-1574

Author(s):

Pinzhu Huang ◽

Yanhong Deng ◽

Jianwei Zhang ◽

Meijin Huang ◽

Jun Huang ◽

...

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Chinese Population ◽

Germline Mutations ◽

Tumor Type ◽

Exact Test ◽

Targeted Next Generation Sequencing ◽

Repair Deficiency ◽

Mutation Burden ◽

Pan Cancer

1574 Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are primarily tested in colorectal (CRC) and endometrial cancer (EC) to aid Lynch Syndrome (LS) diagnosis. A pan-cancer study presented at 2018 ASCO, however, revealed that up to 50% of LS patients had tumors not typically associated with LS, suggesting that patients with an MSI-high (MSI-H) phenotype should proceed to germline testing regardless of tumor type or family history. We thus set out to examine this potentially practice changing notion in Chinese population. Methods: MSI status and germline mutations in MLH1, MSH2, MSH6 and PMS2 genes were determined using a targeted next generation sequencing panel covering 100 MSI loci as well as MMR genes. Tumor mutation burden (TMB) levels were calculated for LS patients with MSI-H and MSS tumors, and intergroup differences were assessed using Mann Whitney U test or Fisher’s exact test. Results: Of 6,288 advanced tumors spanning > 27 cancers, 0.8% (48/6,288) were EC, 21.6% (1,362/6,288) were CRC, and 77.6% (4,878/6,288) were other malignancies. 3.6% (224/6,288) of the samples were found to be MSI-H and 3.5% (217/6,288) harbored MMR mutations (somatic and germline). Germline mutations indicative of LS were identified in 0.1% (8/6,064) of the MSS group and 17% (38/224) of the MSI-H group (p < 0.001). In contrast with the 2018 ASCO report, up to 63.8% of the 224 MSI-H tumors were CRC/EC, and only 8.9% (3/38) of the LS patients had MSI-H non-CRC/EC tumors (1 ovarian clear cell, 1 small bowel, and 1 gastric cancer). LS patients with non-CRC/EC tumors were more likely to be MSS compared to those with CRC/EC (70.0% vs 2.7%, p < 0.001). Alterations in MLH1/ MSH2 were present in 78.3% (36/46) of the LS patients, and they demonstrated significantly better correlation with a MSI-H phenotype than MSH6/PMS2 alterations (94.4% vs. 40.0%, p = 0.0005). Additionally, in line with previous reports showing co-ocurrence of MSI-H and high TMB in gastrointestinal cancers, the LS patients with MSS tumors had a significantly lower median TMB compared with the MSI-H population (4.6 muts/Mb vs. 91.8 muts/Mb, p < 0.001). Conclusions: Our study showed that in Chinese population, CRC/EC still predominated among LS-associated cancers, while non-CRC/EC LS patients were more likely to present with an MSS phenotype. The value of MSI-H/dMMR as a predictor of LS across different tumor types warrant further investigation.

Download Full-text

Germline mutations in MSH2 and ATM gene in patients with GIST (gastrointestinal stromal tumor) and second epitelial tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e23520 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e23520-e23520

Author(s):

Silvia Gasperoni ◽

Laura Papi ◽

Francesca Castiglione ◽

Francesca Gensini ◽

Roberta Sestini ◽

...

Keyword(s):

Genetic Counseling ◽

Lynch Syndrome ◽

Colon Adenocarcinoma ◽

Germline Mutations ◽

Genetic Alterations ◽

Second Primary ◽

Sequencing Analysis ◽

Msh2 Gene ◽

Primary Tumors ◽

Therapeutic Implications

e23520 Background: In adult GISTs are frequently sporadic, while rarely GISTs are linked to Carney Triad and Carney-Stratakis Syndrome and NF1. GISTs with second primary tumors are reported in 4-33% of patients in literature and genetic counseling is suggested to explore an underlying germline mutations pathway. Methods: In our Academic Hospital Centre (EURACAN member) in Florence, Italy, we are following patients with GIST and multiple primary tumors with genetic counseling (72 GISTs with second tumors/185 patients with GIST) and germline analysis of the following genetic panel is performed as clinically indicated: BRCA1, BRCA2, MUTYH, MLH1, MSH2, MSH6, CDH1, ATM, TP53, PTEN, CHECK2, PALB2, BARD1, BRIP1, BLM, RAD51C, RAD51D, XRCC2, PMS2, MRE11A, RAD50, NBN, FAM175A, EPKAM, TSK1, MEN1 by sequencing analysis with Illumina MiSeq by kit multiplicom BRCA Hereditary cancer Mastr plus, and bioinformatic analysis by software SOPHIADDM (Sophia genetics) for point genetic alterations of BRCA1 NM_007294.3, BRCA2 NM_000059.3, MUTYH NM_000249, MSH2 NM_000251, MSH6 NM_000179, CDH1 NM_00444360, ATM NM_000051, TP53 NM_000546, PTEN NM_000314, CHEK2 NM_001005735, PALB2 NM_024675, BARD1 NM_000465, BRIP1 NM_032043, BLM NM_000057, RAD51C NM_002876, RAD51D NM_001142571, XRCC2 NM_005431, PMS2 NM_000535, MRE11A NM_005590, RAD50 NM_006732, NBN NM_002485, FAM175A NM_139076, EPCAM NM_002354, STK1 NM_000455, MEN1 NM_000244 and MLPA (Multiplex Ligation-dependent Probe Amplification) test analysis for patients with kit P087-BRCA1,P045-BRCA2(CHEK2, P248-MLH1-MSH2, P003-MLH1/MSH2, P072-MSH6-MUTYH (MRC-Holland). Results: In 3 patients germline mutations have been observed: 1 patient showed the c.1192dupG, p.(Ala398Glyfs*19) pathogenic mutation in exon 7 of MSH2 gene, confirmed by Sanger Sequencing, 1 patient showed c.565-?_1130+?del mutation consisting in heterozygous 3-4-5-6 exons deletion of MSH2 gene, confirmed by MLPA analysis, and in 1 patient the following ATM alteration has been identified in heterozygosis: ATM c.5319+2T > C, p.(?). In the 2 patients with Lynch syndrome with colon adenocarcinoma (MSI-H), synchronous GISTs (1 patient quadruple WT and 1 patient kit ex 11 mutated ) were diagnosed; in the patient with ATM mutation, the diagnosis of GIST (kit ex 11 mutated) occurred after prostate adenocarcinoma and before colon adenocarcinoma (MSI-H). Conclusions: Our analysis suggests that GIST diagnosis could be tumor-related to multiple hereditary tumor syndromes as Lynch Syndrome and Ataxia-Teleangectasia syndrome, the latter being linked in eterozygosis to tumor susceptibility to breast in female. This report represents a high value in terms of genetic counseling for relatives and in terms of therapeutic implications for the patients.

Download Full-text