scholarly journals Repurposing Non-invasive prenatal testing data; population study of single nucleotide variants associated with colorectal cancer and Lynch syndrome

2021 ◽  
Author(s):  
Natalia Forgacova ◽  
Juraj Gazdarica ◽  
Jaroslav Budis ◽  
Jan Radvanszky ◽  
Tomas Szemes
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Prenatal Testing ◽  
Allelic Frequency ◽  
Plasma Dna ◽  
Single Nucleotide Variants ◽  
Non Invasive ◽  
Slovak Population ◽  
Pathogenic Variants ◽  
Risk Variants

Abstract PURPOSE: In our previous work, we described genomic data generated through non-invasive prenatal testing (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA of pregnant women in Slovakia as a valuable source of population specific data. In the present study, we used these data to determine the population allele frequency of common risk variants located in genes associated with colorectal cancer (CRC) and Lynch syndrome (LS). METHODS: Allele frequencies of identified variants were compared with six world populations to detect significant differences between populations. Finally, we interpreted variants and searched for functional consequences and clinical significance of variants using publicly available databases.RESULTS: Although we could not identify any pathogenic variants associated with CRC or LS in the Slovak population using NIPT data, we observed significant differences in the allelic frequency of risk CRC variants previously reported in GWAS and common variants located in genes associated with LS. CONCLUSION: As Slovakia is the third country with the highest incidence of CRC per 100 000 population in the world, we highlight a need for studies dedicated to the cause of such a high incidence of CRC in Slovakia. We also assume that extensive cross-country data aggregation of NIPT results would represent an unprecedented source of information about human genome variation, also in cancer research.

scholarly journals Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

2019 ◽  
Vol 20 (18) ◽  
pp. 4403 ◽  
Author(s):  
Ondrej Pös ◽  
Jaroslav Budis ◽  
Zuzana Kubiritova ◽  
Marcel Kucharik ◽  
Frantisek Duris ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Copy Number Variants ◽  
Prenatal Testing ◽  
Genomic Data ◽  
Population Diversity ◽  
Clinical Diagnostics ◽  
Plasma Dna ◽  
Non Invasive ◽  
Slovak Population ◽  
Pathogenic Variants

Copy number variants (CNVs) are an important type of human genome variation, which play a significant role in evolution contribute to population diversity and human genetic diseases. In recent years, next generation sequencing has become a valuable tool for clinical diagnostics and to provide sensitive and accurate approaches for detecting CNVs. In our previous work, we described a non-invasive prenatal test (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA for detection of CNV aberrations ≥600 kbp. We reanalyzed NIPT genomic data from 5018 patients to evaluate CNV aberrations in the Slovak population. Our analysis of autosomal chromosomes identified 225 maternal CNVs (47 deletions; 178 duplications) ranging from 600 to 7820 kbp. According to the ClinVar database, 137 CNVs (60.89%) were fully overlapping with previously annotated variants, 66 CNVs (29.33%) were in partial overlap, and 22 CNVs (9.78%) did not overlap with any previously described variant. Identified variants were further classified with the AnnotSV method. In summary, we identified 129 likely benign variants, 13 variants of uncertain significance, and 83 likely pathogenic variants. In this study, we use NIPT as a valuable source of population specific data. Our results suggest the utility of genomic data from commercial CNV analysis test as background for a population study.

scholarly journals Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome

2019 ◽  
Vol 56 (7) ◽  
pp. 462-470 ◽  
Author(s):  
Rachel Pearlman ◽  
Sigurdis Haraldsdottir ◽  
Albert de la Chapelle ◽  
Jon G Jonasson ◽  
Sandya Liyanarachchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Clinical Characteristics ◽  
Population Based ◽  
Pathogenic Variants ◽  
Age Of Diagnosis ◽  
Generation Sequencing ◽  
Mmr Proteins

BackgroundPatients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without MLH1 methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.MethodsWe included patients with CRC from Ohio 2013–2016 and Iceland 2000–2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and MLH1 methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.ResultsOf the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10−4) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10−6) and have multiple LS-associated tumours (OR=6.67, p=3.31×10−5). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.ConclusionsIndividuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.

scholarly journals Prevalence and spectrum of MLH1, MSH2, and MSH6 pathogenic germline variants in Pakistani colorectal cancer patients

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Muhammad Usman Rashid ◽  
Humaira Naeemi ◽  
Noor Muhammad ◽  
Asif Loya ◽  
Jan Lubiński ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Research Centre ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
History Of ◽  
Group 2 ◽  
Colorectal Cancer Patients ◽  
Group 1

Abstract Background Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients. Methods Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2. Results Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected. Conclusion Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

High prevalence of pathogenic variants in individuals with colorectal cancer ≤ age 35.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 576-576 ◽  
Author(s):  
Megan L. Marshall ◽  
Maegan Roberts ◽  
Lisa R. Susswein ◽  
Anna K. McGill ◽  
Zhixiong Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Early Onset ◽  
Statistical Significance ◽  
Age At Onset ◽  
Tumor Location ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Tumor Studies

576 Background: Young age at onset is a hallmark feature of an inherited predisposition to cancer. Recent evidence suggests that the incidence of pathogenic/likely pathogenic variants (PV) in cancer predisposition genes among individuals diagnosed with colorectal cancer (CRC) ≤ age 35 is high, but few studies have examined the frequency identified by multi-gene hereditary cancer panel testing. We report on PV yield and clinical presentation of individuals diagnosed with CRC ≤ 35 years (y). Methods: We retrospectively reviewed test requisition forms and provided pathology reports for 4,727 individuals with CRC who underwent panel testing of, at a minimum, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH. Two-tailed Fisher’s exact tests were used to determine statistically significant differences between groups. Results: Of the 691 individuals diagnosed with CRC ≤35y, 137 PV were identified in 126 individuals (126/691, 18.2%), including 72 with Lynch syndrome, 16 with familial adenomatous polyposis (FAP), five with MUTYH-associated polyposis, four with constitutional mismatch repair deficiency, one with juvenile polyposis syndrome, and one with Peutz-Jeghers syndrome. Thirty-eight additional PVs were identified in other non-CRC genes. Microsatellite instability (MSI) and immunohistochemistry (IHC) results were reported for 277 individuals and were reportedly abnormal in 63. The yield of PV in individuals with abnormal tumor studies was 52.4% (33/63); PV in genes other than the Lynch syndrome-associated genes were identified, commonly in the MSI-H group. While statistical significance was not observed, the positive rate was higher for individuals with non-rectal cancers (colon cancer: 104/534, 19.5%; rectal cancer: 22/157, 14.0%, p = 0.13). Conclusions: In our cohort, 18.2% of individuals diagnosed with CRC ≤35y were found to harbor a PV. Yield increased in those with abnormal MSI/IHC as well as non-rectal tumor location. Hereditary predispositions in patients diagnosed with very early-onset CRC are not limited to Lynch syndrome and FAP. Therefore, individuals with very early-onset CRC may benefit from multi-gene panel testing rather than syndromic-based testing.

scholarly journals No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

2021 ◽  
Vol 10 (13) ◽  
pp. 2856
Author(s):  
Mev Dominguez-Valentin ◽  
John-Paul Plazzer ◽  
Julian R. Sampson ◽  
Christoph Engel ◽  
Stefan Aretz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Urinary Tract ◽  
Lynch Syndrome ◽  
Cancer Surveillance ◽  
Aberrant Splicing ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Splicing Variants ◽  
Endometrial Cancers

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

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