Principles of molecular testing for hereditary cancer

Mighton, Chloe; Lerner‐Ellis, Jordan

doi:10.1002/gcc.23048

Cited by 7 publications

(7 citation statements)

References 248 publications

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“…The cancer development is triggered by the somatic inactivation of the remaining gene copy, be it a deletion (loss of heterozygosity, LOH), a point mutation, or epigenetic silencing. This two-hit mechanism, initially predicted by Alfred G. Knudson, is observed in the majority of HCSs, although some other roots have been described as well [1,2,4].…”

Section: Introductionmentioning

confidence: 82%

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Hereditary Renal Cancer Syndromes

Yanus,

Kuligina,

Imyanitov

2024

Medical Sciences

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Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel–Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt–Hogg–Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

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Section: Introductionmentioning

confidence: 82%

“…There are a few dozen other types of HCSs; however, they have a significantly lower incidence. Indeed, the knowledge on most of the HCS types is limited to the description of several thousand or even several hundred affected individuals with many nuances remaining poorly understood [1,2].…”

Section: Introductionmentioning

confidence: 99%

Hereditary Renal Cancer Syndromes

Yanus,

Kuligina,

Imyanitov

2024

Medical Sciences

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“…Exceptionally high TMB is indicative of the hereditary cancer syndrome associated with the inactivation of MLH1, MSH2, MSH6, PMS2 or other genes. Although we excluded familial CRC cases in our cohort, patients with very high TMB results may require germline genetic testing [ 50 ]. The clinical utility of TMB remains a contentious issue, but it may be wise to look at cases with high TMB, as almost all colorectal tumors arising in patients with Lynch syndrome and sporadic CRCs have high TMB due to MLH1 promoter hypermethylation [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel

Alsolme,

Alqahtani,

Fageeh

et al. 2023

Diagnostics

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Purpose: Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC. Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression. Conclusions: These results may help optimize personalized therapy when drugs specific to a patient’s mutation profile have already been developed.

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“…However, there are some missense mutations, which also lead to BRCA1/2 inactivation, but their actual pathogenic significance is difficult to clarify. Furthermore, the existing multigene NGS assays have not been sufficiently validated for the detection of large gene rearrangements (LGRs), i.e., deletions or duplications of gross portions of the genes [ 36 , 37 ]. Some tumors in BRCA1/2 germline mutation carriers still retain the functional copy of the involved gene; this is particularly characteristic for non-breast-ovarian cancer types [ 38 , 39 ].…”

Section: Homologous Repair Deficiency (Hrd)mentioning

confidence: 99%

“…In addition to the technical caveats of TMB measurement, the clinical utility of TMB remains the subject of discussion. Exceptionally high TMB in carcinogen-unrelated tumors may be an indicator of hereditary cancer syndrome associated with the inactivation of POLD1 , POLE , MUTYH , MMR ( MLH1 , MSH2 , MSH6 , PMS2 ), or some other genes, so in rare circumstances, TMB results may call for germline genetic testing [ 36 ]. TMB is regarded as an appropriate predictive marker for immunotherapy response in non-small cell lung cancer (NSCLC) and cutaneous melanoma [ 78 , 79 , 80 , 81 ].…”

Section: Tumor Mutation Burden (Tmb)mentioning

confidence: 99%

Integrative Genomic Tests in Clinical Oncology

Imyanitov

Sokolenko

2022

IJMS

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Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related “genomic scars” are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.

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Principles of molecular testing for hereditary cancer

Cited by 7 publications

References 248 publications

Hereditary Renal Cancer Syndromes

Hereditary Renal Cancer Syndromes

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel

Integrative Genomic Tests in Clinical Oncology

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