Reduced life expectancy seen in hereditary diseases which predispose to early-onset tumors

Evans, D. Gareth; Ingham, Sarah

doi:10.2147/tacg.s35605

Cited by 18 publications

(19 citation statements)

References 77 publications

(138 reference statements)

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“…Firstly, the median age of MM diagnosis was significantly younger among the 9 BAP1 mutation carriers as compared to non-carriers (58 vs. 68 years). This earlier age of tumor onset is similar to that observed in other cancer predisposition syndromes (31) (33). Secondly, there was an overrepresentation of peritoneal MMs (5 of 9) and a tendency for epithelioid MM among the mutation carriers compared to non-carriers (16).…”

Section: Unique MM Clinical Characteristics Associated With Bap1 Mutasupporting

confidence: 84%

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BAP1, a tumor suppressor gene driving malignant mesothelioma

Cheung

Testa

2017

Transl. Lung Cancer Res.

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Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci CDKN2A and NF2, respectively. Only relatively recently was the BAP1 gene determined to be the driver gene at 3p21.1 that is somatically inactivated. In 2011, we reported germline mutations in BAP1 in two families with a high incidence of mesothelioma and other cancers such as uveal melanoma (UM). As a result of a flurry of research activity over the last 5-6 years, the BAP1 gene is now firmly linked causally to a novel tumor predisposition syndrome (TPDS) characterized by increased susceptibility to mesothelioma, UM, cutaneous melanoma (CM) and benign melanocytic tumors, as well as several other cancer types. Moreover, results from recent in vivo studies with genetically engineered Bap1-mutant mouse models and new functional studies have provided intriguing biological insights regarding BAP1's role in tumorigenesis. These and other recent findings offer new possibilities for novel preventative and therapeutic strategies for MM patients.

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Section: Unique MM Clinical Characteristics Associated With Bap1 Mutasupporting

confidence: 84%

“…31, a region that is frequently deleted in lung carcinomas and many other cancers (7). The group identified somatic BAP1 deletions/mutations in two non-small cell lung cancer and one small cell lung cancer cell lines.…”

Section: Somatic and Germline Mutations Of Bap1mentioning

confidence: 99%

BAP1, a tumor suppressor gene driving malignant mesothelioma

Cheung

Testa

2017

Transl. Lung Cancer Res.

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“…3,4 As a result, patients with LS have a decreased life expectancy compared with nonaffected individuals. 5 Diagnosing LS in endometrial cancer (EC) patients is an important step in clinical management. It allows for cascade testing to diagnose family members who may also have the disease.…”

Section: Introductionmentioning

confidence: 99%

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Ryan

Glaire

Blake

et al. 2019

Genetics in Medicine

161

144

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Purpose: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS. Methods: Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixedeffects meta-analysis models. I 2 score was used to assess heterogeneity across studies. Results: Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I 2 : 71%) and 0.26 (95% CI 0.25-0.27, I 2 : 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I 2 : 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses. Conclusion: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.

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“…Individuals who have Li–Fraumeni syndrome (LFS; MIM# 151623) have a high risk of developing sarcomas, brain tumors, adrenocortical carcinomas, premenopausal breast cancer, leukemia, and other cancers early in life (Sorrell, Espenschied, Culver, & Weitzel, ). Though no studies have directly measured life expectancy in LFS, it is known to be severely reduced (Evans & Ingham, ). Germline pathogenic variants (PVs) in TP53 are the most common cause of LFS.…”

Section: Introductionmentioning

confidence: 99%

A substantial proportion of apparently heterozygousTP53pathogenic variants detected with a next‐generation sequencing hereditary pan‐cancer panel are acquired somatically

et al. 2019

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Previous analysis of next‐generation sequencing (NGS) hereditary pan‐cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10% and 30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging‐related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele frequency 30–70%) were offered follow‐up testing to confirm variant origin. Ninety‐eight probands had samples submitted for follow‐up family member testing, fibroblast testing, or both. The apparent heterozygous germline TP53 PV was not detected in 32.6% (15/46) of submitted fibroblast samples, indicating that it was acquired somatically, either through clonal hematopoiesis or via constitutional mosaicism. Notably, no individuals with confirmed germline or likely germline TP53 PVs met classic Li–Fraumeni syndrome (LFS) criteria, only 41% met Chompret LFS criteria, and 59% met neither criteria, based upon provider‐reported personal and family cancer history. Comprehensive reporting of TP53 PVs detected using NGS, combined with follow‐up analysis to confirm variant origin, is advised for clinical testing laboratories. These findings underscore the investment required to provide individuals and family members with clinically accurate genetic test results pertaining to their LFS risk.

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Reduced life expectancy seen in hereditary diseases which predispose to early-onset tumors

Cited by 18 publications

References 77 publications

BAP1, a tumor suppressor gene driving malignant mesothelioma

BAP1, a tumor suppressor gene driving malignant mesothelioma

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

A substantial proportion of apparently heterozygousTP53pathogenic variants detected with a next‐generation sequencing hereditary pan‐cancer panel are acquired somatically

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