The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Fierheller, Caitlin T.; Alenezi, Wejdan M.; Tonin, Patricia N.

doi:10.3390/cancers13143406

Cited by 10 publications

(38 citation statements)

References 165 publications

(273 reference statements)

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“…Several studies on linkage analysis in non BRCA1/2 families have been conducted in other populations [ 20 – 25 ]. However, the fact that these findings do not replicate in other populations is not surprising given the uniqueness of this Sri Lankan data set.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka

et al. 2022

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Objective Although linkage studies have been utilized for the identification of variants associated with cancer in the world, little is known about their role in non BRCA1/2 individuals in the Sri Lankans. Hence we performed linkage analysis to identify susceptibility loci related to the inherited risk of cancer in a cohort of Sri Lankans affected with hereditary breast cancer. The Illumina global screening array having 654,027 single nucleotide polymorphism markers was performed in four families, in which at least three individuals within third degree relatives were affected by breast cancer. Two-point parametric linkage analysis was conducted assuming disease allele frequency of 1%. Penetrance was set at 90% for carriers with a 10% phenocopy rate. Results Thirty-one variants exhibited genome-wide suggestive HLODs. The top overall HLOD score was at rs1856277, an intronic variant in MYO16 on chromosome 13. The two most informative families also suggested several candidate linked loci in genes, including ERAP1, RPRM, WWOX, CDH1, EXOC1, HUS1B, STIM1 and TUSC1. This study provides the first step in identifying germline variants that may be involved in risk of cancer in cancer-aggregated non-BRCA1/2 families from the understudied Sri Lankan population. Several candidate linked regions showed suggestive evidence of linkage to cancer risk.

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Section: Discussion/conclusionmentioning

confidence: 99%

Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka

et al. 2022

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“…We have proposed a strategy for identifying candidate variants in new cancer predisposing genes that involves the investigation of cancer families from populations exhibiting genetic drift ( 33 ). Over time, rare PVs in such populations could attain disproportionally high carrier frequencies of rare risk variants relative to the general population ( 34 , 35 ).…”

Section: Introductionmentioning

confidence: 99%

“…Our research of French Canadians (FC) from the Quebec population of Canada, identified RECQL ( 37 ) and FANCI ( 24 ) as new candidate BC or OC predisposing genes, respectively. Genetic drift in the FCs of Quebec has been attributed to common ancestors as a result of the geographic isolation and multiple waves of expansion of European settlers from France since 1608 ( 33 – 35 , 38 , 39 ). Investigating these populations facilitates the characterization of deleterious variants in known or candidate cancer predisposing genes as all types of variants could be investigated and not only LoF variants ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

“…Genetic drift in the FCs of Quebec has been attributed to common ancestors as a result of the geographic isolation and multiple waves of expansion of European settlers from France since 1608 ( 33 – 35 , 38 , 39 ). Investigating these populations facilitates the characterization of deleterious variants in known or candidate cancer predisposing genes as all types of variants could be investigated and not only LoF variants ( 33 ). A small number of PVs in BRCA1 and BRCA2 ( 40 , 41 ) and one in each of PALB2 ( 42 ), RAD51C ( 43 ) and RAD51D ( 43 , 44 ) have been shown to be frequently occurring in FC OC and/or BC cases versus population-matched controls.…”

Section: Introductionmentioning

confidence: 99%

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Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

et al. 2023

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Not all familial ovarian cancer (OC) cases are explained by pathogenic germline variants in known risk genes. A candidate gene approach involving DNA repair pathway genes was applied to identify rare recurring pathogenic variants in familial OC cases not associated with known OC risk genes from a population exhibiting genetic drift. Whole exome sequencing (WES) data of 15 OC cases from 13 families tested negative for pathogenic variants in known OC risk genes were investigated for candidate variants in 468 DNA repair pathway genes. Filtering and prioritization criteria were applied to WES data to select top candidates for further analyses. Candidates were genotyped in ancestry defined study groups of 214 familial and 998 sporadic OC or breast cancer (BC) cases and 1025 population-matched controls and screened for additional carriers in 605 population-matched OC cases. The candidate genes were also analyzed in WES data from 937 familial or sporadic OC cases of diverse ancestries. Top candidate variants in ERCC5, EXO1, FANCC, NEIL1 and NTHL1 were identified in 5/13 (39%) OC families. Collectively, candidate variants were identified in 7/435 (1.6%) sporadic OC cases and 1/566 (0.2%) sporadic BC cases versus 1/1025 (0.1%) controls. Additional carriers were identified in 6/605 (0.9%) OC cases. Tumour DNA from ERCC5, NEIL1 and NTHL1 variant carriers exhibited loss of the wild-type allele. Carriers of various candidate variants in these genes were identified in 31/937 (3.3%) OC cases of diverse ancestries versus 0-0.004% in cancer-free controls. The strategy of applying a candidate gene approach in a population exhibiting genetic drift identified new candidate OC predisposition variants in DNA repair pathway genes.

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“…However, this risk increases up to 15%-45% for germline BRCA1 pathogenic variant carriers, and 10%-20% for BRCA2 pathogenic variant carriers (6). Among all hereditary OC patients, 15%-35% of pathogenic variations may be present in other tumor suppressor genes or oncogenes including mismatch repair (MMR) genes, TP53, ATM, CHEK2, PALB2, RAD50, and BRIP1 (5,7). Identifying the underlying molecular defects in ovarian cancer is an important approach for the medical management of patients and guidance regarding treatment options, and this study aimed to reveal the relationship between genetic variations and clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

Germline Screening of Cancer-Related Genes in Turkish Ovarian Cancer Patients

Ateş¹,

Alavanda²,

Geçkinli³

et al. 2022

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Objective: Ovarian cancer (OC) is one of the most fatal types of cancer and affects 1%-1.5% of women worldwide. The most common genes causing OC are the BRCA1 and BRCA2 genes. However, improvements in next-generation sequencing (NGS) technologies have allowed for screening of the various genes related to hereditary cancer syndromes. The aim of this study was to evaluate cancer-related gene variations among cases of ovarian cancer. Materials and Methods:The study evaluated 63 cases that were referred to the Marmara University Pendik Training and Research Hospital Genetic Diseases Diagnostic Center between 2016-2021 with a diagnosis of OC for germline variations in 25 cancer-related genes using NGS. Large intragenic rearrangements of the BRCA1 and BRCA2 genes were screened using multiplex ligation-dependent probe amplification (MLPA). Results:The study detected 12 distinct pathogenic variations in the BRCA1, BRCA2, BRIP1, and RAD50 genes in 13 OC cases. Four of the 13 cases involved copy number variations that included at least one exon of the BRCA1 gene. Conclusion:This study detected pathogenic BRCA1 variations to be the leading cause of hereditary OC. The study showed just screening for BRCA1 to reveal the underlying hereditary defect in 76.9% of the cases, which seems higher compared to literature. More studies involving larger cohorts are necessary to figure out the exact frequency of BRCA1 variations in Turkish OC cases.

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The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Cited by 10 publications

References 165 publications

Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka

Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka

Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

Germline Screening of Cancer-Related Genes in Turkish Ovarian Cancer Patients

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