The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk
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Abstract Background Germline mutations represent a high risk of hereditary cancers in population. The landscape and characteristics of germline mutations in genitourinary cancer are largely unknown, and their correlation with patient prognosis has not been defined. Methods Variant data and relevant clinical data of 10,389 cancer patients in The Cancer Genome Atlas (TCGA) database was downloaded. The subset of data of 206 genitourinary cancer patients containing bladder urothelial carcinoma (BLCA), kidney chromophobe carcinoma (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and prostate adenocarcinoma (PRAD) cancer with germline mutation information was filtered for further analysis. Variants were classified into pathogenic, likely pathogenic and non-pathogenic categories based on American College of Medical Genetics and Genomics (ACMG) guidelines. Genome Aggregation Database (gnomAD) database was used to assist risk analysis. Results There were 48, 7, 44, 45 and 62 patients with germline mutations identified in BLCA, KICH, KIRC, KIRP and PRAD, respectively. Pathogenic germline mutations from 26 genes and likely pathogenic mutations from 33 genes were revealed. GJB2 , MET , MUTYH and VHL mutations ranked top in kidney cancers, and ATM and CHEK2 mutations ranked top for bladder cancer, while ATM and BRCA1 mutations ranked top for prostate cancer. Frameshift, stop gained and missense mutations were the predominant mutation types. BLCA exhibited the highest ratio of stop gained mutations (22/48 = 45.8%). No difference in patient age was found among pathogenic, likely pathogenic and non-pathogenic groups for all cancer types. The number of male patients far overweight female patients whether PRAD was included ( P = 0) or excluded ( P < 0.001). Patients with pathogenic or likely pathogenic germline mutations exhibited significantly worse overall survival rate than the non-pathogenic group for all genitourinary cancers. More important, analyses assisted by gnomAD database revealed that pathogenic or likely pathogenic germline mutations significantly increased the risk for genitourinary cancer in population, with the odds ratio at 14.88 (95%CI 11.80–18.77) and 33.18 (95%CI 24.90–44.20), respectively. Conclusions The germline mutational status for genitourinary cancers has been comprehensively characterized. Pathogenic and likely pathogenic germline mutations increased the risk and indicated poor prognosis of genitourinary cancers.Keywords:
Kidney cancer
CHEK2
MLH1
MLH1
MSH2
Immunostaining
Microsatellite Instability
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An analysis of a series of population studies and the results of molecular genetic studies show that one of the predisposing factors in the development of cancer is the presence of a germline mutation. Monoallelic mutations in PALB2, CHEK2, and ATM may be associated with an increased risk of developing cancers other than breast cancer, as has been observed for BRCA1 and BRCA2, ovarian, and prostate cancers. A large body of evidence has now accumulated indicating that carriers of germline CHEK2 mutations face an increased risk of a variety of cancers that exhibit some specific clinicopathological characteristics. The paper presents data on the significance of germline mutations in the CHEK2 gene, as well as a clinical observation of a patient with a germline mutation in the CHEK2 gene and a developed malignant neoplasm. The above clinical observation makes it possible to establish a link between a germline mutation in the CHEK2 gene and the development of a rare malignant neoplasm at a young age in a patient. The paper reflects the need for genetic testing in healthy relatives of the patient for the presence of a germline mutation in the CHEK2 gene, which will allow for thorough screening measures for the early detection of malignant neoplasms.
CHEK2
Li–Fraumeni syndrome
PALB2
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Purpose. Recently, pheochromocytomas and paragangliomas (PPGLs) have been strongly suspected as hereditary tumors, as approximately 40% of patients carry germline mutations. In the cancers where defects occur to corrupt DNA repair and facilitate tumorigenesis, a CHEK2 strong association has been observed. Therefore, the purpose of this study was to investigate the effect of CHEK2 mutations for its possible pathogenicity in PPGLs. Methods. Four patients with CHEK2 mutations were recruited, as previously detected by the whole exome sequencing. Sanger sequencing was used to verify the germline mutations as well as the loss of heterozygosities (LOHs) in their somatic DNAs. Immunohistochemistry was used to analyze the expression of CHEK2 and its downstream target p53 Ser20 (phosphorylated p53). Results. The average age of studied patients was 44.25 ± 11.18 years, at the time diagnosis. One patient had multiple tumors which recurred quickly, while two patients had distant metastasis. None of the patient had any relevant family history. Four germline CHEK2 mutations were identified (c.246_260del; c.715G > A; c.1008+3A > T; and c.1111C > T). All the patients were predicted to have either pathogenic or suspected pathogenic mutations. There was no LOH of CHEK2 gene in somatic DNAs found. Additionally, neither CHEK2 proteins nor its downstream target p53 Ser20 were expressed in the tumor tissues. The inactivation of CHEK2 leads to the decrease in the p53 phosphorylation, which might promote tumorigenesis. Conclusions. For the first time, CHEK2 was identified as a susceptibility gene for PPGLs. However, the penetrance of CHEK2 gene with genotype-phenotype correlation needs to be investigated.
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Penetrance
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It has recently been suggested that the frequency of the germline CHEK2*1100delC mutation is higher among breast cancer families with colorectal cancer, although the mutation does not seem to be significantly associated with familial colorectal cancer. Five hundred and sixty-four familial colorectal tumours were studied for expression of CHEK2 using tissue microarrays and an antibody against the NH2-terminal SQ regulatory domain of the CHEK2 protein. Normal colonic tissue from patients whose tumours showed loss of CHEK2 expression was investigated further using fragment and sequence analysis for the presence of a CHEK2*1100delC mutation and five other (R117G, R137Q, R145W, I157T, and R180H) known germline variants in CHEK2. Twenty-nine tumours demonstrated loss of expression for CHEK2. Analysis of matched normal colonic tissue from these patients revealed germline CHEK2*1100delC mutation in three cases. In two of these, the mutation was heterozygous but, interestingly, the third patient proved to be homozygous for the deletion, using six different primer pair combinations. None of the other tested germline variants were identified. No CHEK2*1100delC mutations were found in patients whose tumours stained positive. Homozygosity for the CHEK2*1100delC mutation appears not to be lethal in humans. No severe clinical phenotype was apparent, although the patient died from colonic carcinoma at age 52 years. This observation is in line with recent knockout mouse models, although in the latter, cellular defects in apoptosis and increased resistance to irradiation seem to exist. It is also concluded that CHEK2 protein abrogation is not caused by the CHEK2 germline variants R117G, R137Q, R145W, I157T, and R180H in familial colorectal cancer.
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Checkpoint Kinase 2
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Microsatellite Instability
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Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations of genes encoding for proteins of the mismatch repair (MMR) machinery. The majority of mutations occur in the MLH1 and MSH2 genes, and consist of splice-site, frameshift and nonsense changes, leading to loss of protein function. In this study, we screened 7 HNPCC families for MLH1/MSH2 mutations. Sequence changes were identified in 5 families. Four alterations were novel 1- or 2-bp deletions or insertions causing a frameshift and appearance of premature stop codons (MLH1: c.597-598delGA, c.1520-1521insT; MSH2: c.1444delA, c.119delG). The four small insertions/ deletions were located within stretches of simple repeated sequences. By reviewing the HNPCC mutation database, we found that the majority of 1-2 bp frameshift mutations similarly affects simple repetitive stretches, pointing to DNA polymerase slippage during replication as the most likely source of such errors. We also evaluated microsatellite instability (MSI) in a breast carcinoma (BC) from an MLH1 mutation carrier. While a colon cancer from the same individual showed MSI, the BC specimen was MSI-negative, indicating that development of the latter tumor was unrelated to MMR impairment, despite presence of a constitutional MLH1 mutation. Hum Mutat 17:521, 2001. © 2001 Wiley-Liss, Inc.
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Several studies clearly demonstrate increased cancer risks associated with pathogenic variants in certain genes. BRCA1 and BRCA2 are perhaps the best known, but many other genes have been associated with increased cancer risks, including but not limited to TP53, PTEN, CDH1, PALB2, MLH1, MSH2, MSH6, ATM, STK11, CHEK2, BRIP1, RAD51C, and RAD51D. National Comprehensive Cancer Network guidelines include management recommendations for patients carrying pathogenic variants in these genes. Both tumor/site-specific and "pan-cancer" panels are available to identify patients at increased risk.
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PALB2
MLH1
MSH6
MSH2
STK11
CDH1
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Given recent increases in the proportion of early-onset colorectal cancer (CRC), researchers are urgently working to establish a multi-gene screening test for both inherited and sporadic cancer-susceptible individuals. However, the incidence and spectrum of germline mutations in young sporadic CRC patients in East Asian countries and, especially, in sporadic polyp carriers and normal individuals are unknown. Peripheral blood samples were collected from 43 colonoscopy-proved normal controls and from 50 polyp patients and 49 CRC patients with no self-reported family history of cancer. All participants were under 50 years old. Next-generation sequencing with a panel of 30 CRC-associated susceptibility genes was employed to detect pathogenic germline mutations. The germline mutation carrier rates were 2.3%, 4.0%, and 12.2% in the normal, polyp, and cancer groups, respectively. A total of seven different mutations in six DNA repair pathway-related genes (MLH1, BRCA1, BRCA2, CHEK2, BLM, and NTHL1) were detected in nine participants. One frameshift mutation in BRCA2 and one frameshift mutation in the CHEK2 gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in MLH1 and one in BRCA1. Three mutations (MLH1 p.Arg265Cys, MLH1 p.Tyr343Ter and CHEK2 p.Ile158TyrfsTer10) were each found in two independent patients and were considered “founder” mutations. This is the first report to demonstrate high percentage of germline mutations in young sporadic colorectal polyp, CRC, and general populations. A multi-gene screening test is warranted for the proactive identification of cancer-predisposed individuals.
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CHEK2
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5084 Background: The intersection between germline and somatic genomics is an evolving field in which germline mutations may predispose to unique patterns of subsequent somatic mutations in cancer. Germline mutations in CHEK2, involved in cell cycle regulation and DNA damage response, are associated with an increased risk of prostate cancer (PCa), while somatic-only CHEK2 alterations in PCa are rare. The association of germline CHEK2 (g CHEK2)-altered PCa with somatic mutations is unknown, and may inform hypotheses about the etiology of these cancers. Methods: Germline DNA sequencing of 1,042 consecutive PCa patients (pts) from the public SignalDB database (www.signaldb.org) was analyzed for prevalence of pathogenic g CHEK2 mutations and was compared to individuals from the general population estimated by the ExAC database (containing 53,105 germline exomes). A separate cohort of 33 PCa pts from Johns Hopkins (JH) with known g CHEK2 mutations and available somatic tumor DNA sequencing (from primary prostatic tissue) was used to assess the association of g CHEK2 mutations with somatic mutations in genes that are recurrently altered in PCa ( TP53, RB1, PTEN, ATM, BRCA1/2, and CDK12); the prevalence of these somatic alterations was compared to those in 333 unselected PCa pts from the TCGA cohort. Somatic biallelic inactivation of CHEK2 was analyzed in a subset of pts. After uncovering a potential link between g CHEK2 and somatic CDK12 mutations, we studied a cohort of 69 pts with somatic CDK12 mutations where germline data were also available. Results: 28 of 1,042 (2.7%) PCa pts from SignalDB had a pathogenic g CHEK2 mutation, compared to a population prevalence (in ExAC) of 1.4% (750 of 53,105) (RR 1.9, 95%CI 1.3–2.8, P< 0.001). Strikingly, only 23.8% of pts from SignalDB with g CHEK2 mutations had biallelic inactivation in the tumor . Furthermore, none of the 33 g CHEK2 pts from the JH cohort had evidence of somatic LOH. There were no differences in mutation prevalences involving TP53, RB1, PTEN, ATM, and BRCA1/2 between g CHEK2-altered and non-altered PCa pts. Unexpectedly, 5 of 33 (15%) g CHEK2-altered pts from the JH cohort had a somatic CDK12 mutation, compared to only 3 of 333 CDK12 mutations (1%) in unselected PCa pts from the TCGA cohort (RR 16.8, 95%CI 4.2–67, P< 0.001). Conversely, 11 of 69 (16%) pts with a somatic CDK12 mutation harbored a pathogenic g CHEK2 mutation, compared to 28 of 1,042 (2.7%) unselected PCa pts from SignalDB (RR 5.9, 95%CI 3.1–11.4, P< 0.001). Conclusions: Prostate cancers from g CHEK2-altered pts are infrequently characterized by biallelic CHEK2 inactivation and may be enriched for somatic CDK12 mutations, suggesting a unique mechanism of carcinogenesis that is different from g BRCA2-altered pts. Conversely, somatic CDK12-mutated cancers may be enriched for g CHEK2 mutations. The co-occurrence of CHEK2 and CDK12 mutations suggests a synergistic role in promoting cancer growth.
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Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome
Abstract Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1 . We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using co mbined b isulphite r estriction a nalysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Lynch Syndrome
MSH2
Microsatellite Instability
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