Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

AbstractAlong with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73–1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

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Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

10.1101/2021.02.22.21250719 ◽

2021 ◽

Author(s):

Yoon Young Choi ◽

Su-Jin Shin ◽

Jae Eun Lee ◽

Lisa Madlensky ◽

Seung-Tae Lee ◽

...

Keyword(s):

Lynch Syndrome ◽

Early Onset ◽

Cancer Susceptibility ◽

Multiple Primary Cancers ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

Predisposition Genes ◽

Synchronous Cancers ◽

Prevalence Of Cancer

AbstractBackgroundAlong with early onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown.MethodsWe screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early onset MPC of stomach and colorectum were further evaluated for at DNA repair and cancer related genes using both normal (germline) and tumor (somatic) whole exome sequencing.ResultsAmong 71 patients with MPCs, variants predicted to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n=10), MSH6 (n=2), PMS2 (n=2), and MSH2 (n=1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5, including a rare East-Asian specific variant, were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR=31.6, p=0.001). Additional evaluation of bi-allelic alterations in the tumor correctly identified LS genes in LS patients and candidates genes in non-LS patients including high-confidence LoF variants in 2 patients, FANCG (c.307+1G>C) and CASP8 (p.R221Sfs*17) both accompanied by somatic loss of heterozygosity in a gastric and a colorectal tumor, respectively.ConclusionsThe results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset patients. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

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Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

npj Breast Cancer ◽

10.1038/s41523-021-00279-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Na Li ◽

Belle W. X. Lim ◽

Ella R. Thompson ◽

Simone McInerny ◽

Magnus Zethoven ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Candidate Genes ◽

Familial Aggregation ◽

Loss Of Function ◽

Cancer Data ◽

Pathogenic Variants ◽

New Genes ◽

Predisposing Genes ◽

Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107347 ◽

2021 ◽

pp. jmedgenet-2020-107347

Author(s):

D Gareth Evans ◽

Elke Maria van Veen ◽

Helen J Byers ◽

Sarah J Evans ◽

George J Burghel ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Ductal Carcinoma ◽

Cancer Genes ◽

Early Onset Breast Cancer ◽

Younger Women ◽

Pathogenic Variants ◽

Younger Age ◽

Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

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CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz103 ◽

2019 ◽

Vol 25 (11) ◽

pp. 1788-1795 ◽

Cited By ~ 8

Author(s):

Thomas Magg ◽

Anna Shcherbina ◽

Duran Arslan ◽

Mukesh M Desai ◽

Sarah Wall ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Mononuclear Cells ◽

Severe Disease ◽

Effector Memory ◽

Loss Of Function ◽

Peripheral Blood Mononuclear ◽

Whole Exome ◽

Inflammatory Bowel

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

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Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

International Journal of Molecular Sciences ◽

10.3390/ijms21020516 ◽

2020 ◽

Vol 21 (2) ◽

pp. 516 ◽

Cited By ~ 5

Author(s):

Lisa Gianesello ◽

Monica Ceol ◽

Loris Bertoldi ◽

Liliana Terrin ◽

Giovanna Priante ◽

...

Keyword(s):

Dent Disease ◽

Low Molecular Weight ◽

Disease Genes ◽

Loss Of Function ◽

Clcn5 Gene ◽

Pathogenic Variants ◽

Whole Exome ◽

Low Molecular Weight Proteins ◽

Clcn5 Mutations

Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

Frontiers in Genetics ◽

10.3389/fgene.2021.690216 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Liu ◽

Hongke Ding ◽

Tizhen Yan ◽

Ling Liu ◽

Lihua Yu ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Facial Features ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

Cognitive Delay ◽

Whole Exome ◽

Before And After ◽

Exon Deletion

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

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Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Neurology Genetics ◽

10.1212/nxg.0000000000000558 ◽

2021 ◽

Vol 7 (2) ◽

pp. e558

Author(s):

Daphne J. Smits ◽

Rachel Schot ◽

Martina Wilke ◽

Marjon van Slegtenhorst ◽

Marie Claire Y. de Wit ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Variants ◽

Brain Mri ◽

Cerebellar Vermis ◽

Compound Heterozygous ◽

Loss Of Function ◽

Functional Studies ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

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One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106189 ◽

2019 ◽

Vol 57 (1) ◽

pp. 53-61 ◽

Cited By ~ 4

Author(s):

Florentia Fostira ◽

Irene Kostantopoulou ◽

Paraskevi Apostolou ◽

Myrto S Papamentzelopoulou ◽

Christos Papadimitriou ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Gene Panel ◽

Control Analysis ◽

Loss Of Function ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Clinical Changes

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

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Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1520 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1520-1520

Author(s):

Rachel Rosenblum ◽

Sabrina A. Suckiel ◽

Gillian M. Belbin ◽

Sinead Cullina ◽

Judy H. Cho ◽

...

Keyword(s):

Lynch Syndrome ◽

Diagnostic Criteria ◽

Sequence Data ◽

Genetic Identification ◽

European Ancestry ◽

Gene Variants ◽

Loss Of Function ◽

Mmr Genes ◽

Pathogenic Variants ◽

Increased Risk

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.

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