The simplest explanation does not have to be preferred: co-occurrence of pathogenic variants in cancer-predisposing 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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Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽

10.3390/cancers13153857 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3857

Author(s):

Pilar Mur ◽

Nuria Bonifaci ◽

Anna Díez-Villanueva ◽

Elisabet Munté ◽

Maria Henar Alonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Early Onset ◽

Low Risk ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Pathogenic Variants ◽

Predisposing Genes ◽

The Mean ◽

Early Onset Colorectal Cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

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Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels

Scientific Reports ◽

10.1038/s41598-019-57080-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Adela Chirita-Emandi ◽

Nicoleta Andreescu ◽

Cristian G. Zimbru ◽

Paul Tutac ◽

Smaranda Arghirescu ◽

...

Keyword(s):

Pediatric Patients ◽

Pathogenic Variants ◽

Predisposing Genes

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Germinal defects of SDHx genes in patients with isolated pituitary adenoma

Acta Endocrinologica ◽

10.1530/eje-20-0054 ◽

2020 ◽

Vol 183 (4) ◽

pp. 369-379

Author(s):

Grégory Mougel ◽

Arnaud Lagarde ◽

Frédérique Albarel ◽

Wassim Essamet ◽

Perrine Luigi ◽

...

Keyword(s):

Genetic Testing ◽

Pituitary Adenoma ◽

Family History ◽

Age Of Onset ◽

Personal History ◽

Pathogenic Variants ◽

Predisposing Genes ◽

History Of ◽

New Gateway

Background: The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

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Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes

EBioMedicine ◽

10.1016/j.ebiom.2020.103033 ◽

2020 ◽

Vol 60 ◽

pp. 103033

Author(s):

Keijiro Mizukami ◽

Yusuke Iwasaki ◽

Eiryo Kawakami ◽

Makoto Hirata ◽

Yoichiro Kamatani ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Genetic Characterization ◽

Carrier Status ◽

Pathogenic Variants ◽

Predisposing Genes

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Use of sanger and next-generation sequencing to screen for mosaic and intronic APC variants in unexplained colorectal polyposis patients

Familial Cancer ◽

10.1007/s10689-021-00236-2 ◽

2021 ◽

Author(s):

Fadwa A. Elsayed ◽

Carli M. J. Tops ◽

Maartje Nielsen ◽

Hans Morreau ◽

Frederik J. Hes ◽

...

Keyword(s):

Next Generation Sequencing ◽

Sanger Sequencing ◽

Colorectal Polyps ◽

Adenomatous Polyposis ◽

Next Generation ◽

Colorectal Polyposis ◽

Pathogenic Variants ◽

Predisposing Genes ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

AbstractIn addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis. In this study, we investigated 80 unexplained colorectal polyposis patients without germline pathogenic variants in known polyposis predisposing genes to detect mosaic and deep intronic APC variants. All patients developed more than 50 colorectal polyps, with adenomas being predominantly observed. To detect APC mosaicism, we performed next-generation sequencing (NGS) in leukocyte DNA. Furthermore, using Sanger sequencing, the cohort was screened for the following previously reported deep intronic pathogenic germline APC variants: c.1408 + 731C > T, p.(Gly471Serfs*55), c.1408 + 735A > T, p.(Gly471Serfs*55), c.1408 + 729A > G, p.(Gly471Serfs*55) and c.532-941G > A, p.(Phe178Argfs*22). We did not detect mosaic or intronic APC variants in the screened unexplained colorectal polyposis patients. The results of this study indicate that the deep intronic APC variants investigated in this study are not a cause of colorectal polyposis in this Dutch population. In addition, NGS did not detect any further mosaic variants in our cohort.

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Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study

The Lancet Gastroenterology & Hepatology ◽

10.1016/s2468-1253(18)30079-7 ◽

2018 ◽

Vol 3 (7) ◽

pp. 489-498 ◽

Cited By ~ 23

Author(s):

Eleanor Fewings ◽

Alexey Larionov ◽

James Redman ◽

Mae A Goldgraben ◽

James Scarth ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Pathogenic Variants ◽

Whole Exome ◽

Predisposing Genes ◽

Cdh1 Mutation

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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

Cancers ◽

10.3390/cancers13143406 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3406

Author(s):

Caitlin T. Fierheller ◽

Wejdan M. Alenezi ◽

Patricia N. Tonin

Keyword(s):

Ovarian Cancer ◽

Genetic Architecture ◽

French Canadian ◽

Cancer Syndrome ◽

French Canadians ◽

Brca1 And Brca2 ◽

Genetic Analyses ◽

Pathogenic Variants ◽

Predisposing Genes

The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

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Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls

10.1101/2020.03.15.989947 ◽

2020 ◽

Author(s):

Masashi Fujita ◽

Xiaoxi Liu ◽

Yusuke Iwasaki ◽

Chikashi Terao ◽

Sadaaki Takata ◽

...

Keyword(s):

Family History ◽

Mismatch Repair ◽

Universal Screening ◽

Screening Strategy ◽

Mismatch Repair Genes ◽

Germline Variants ◽

Pathogenic Variants ◽

Predisposing Genes ◽

History Of ◽

Repair Genes

AbstractBackground & AimsColorectal cancer (CRC) is one of the most common cancers in Western countries and Japan. Currently, a few % of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes, predominantly the DNA mismatch repair genes. To establish a universal screening strategy for hereditary CRCs, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.MethodsWe analyzed the coding regions of 27 cancer-predisposing genes, including mismatch repair genes, APC, and BRCA1/2, in 12,503 unselected Japanese CRC patients and 23,705 controls aged ≥ 60 years without any personal or family history of cancer by target sequencing and genome-wide SNP chip data. Their clinical significance was assessed using ClinVar and the guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP).ResultsWe identified 4,804 variants in the 27 genes and annotated them as 397 pathogenic variants, 941 benign variants, and 3,466 variants of uncertain significance, of which 43.6% were registered in neither ClinVar nor dbSNP. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant of the 27 genes. The pathogenic variants of MSH2 (odds ratio (OR) =18.1), MLH1 (OR=8.6), MSH6 (OR=4.9), APC (OR=49.4), BRIP1 (OR=3.6), BRCA1 (OR=2.6), BRCA2 (OR=1.9), and TP53 (OR=1.7) were significantly associated with CRC development in the Japanese population (P-values < 0.01, FDR<0.05). Furthermore, we confirmed copy number variants (CNVs) of MSH2/EPCAM, MLH1, and APC by multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR in this cohort (n = 23), including whole gene duplications of MSH2 and APC. These pathogenic variants were significantly associated with the diagnostic age and personal/family history of other types of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes.ConclusionsThis is the largest study of CRC heredity in the Asian population and would contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. Universal screening for CRC risk should be assessed in multiple genes, including BRCA1/2 and BRIP1. These data would facilitate risk assessment of cancer and optimize the screening strategy.

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