Updates in the field of hereditary nonpolyposis colorectal cancer

Peltomäki, Païvi; Olkinuora, Alisa; Nieminen, Taina T.

doi:10.1080/17474124.2020.1782187

Cited by 20 publications

(13 citation statements)

References 137 publications

(166 reference statements)

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“…Subsequent studies have since identified three RPS20 mutations in familial CRC cases ( 96 , 97 ) and two in Diamond-Blackfan anemia (DBA) patients ( 98 ). Available experience suggests that only a small fraction of FCCTX susceptibility genes have been discovered so far, and that private genes and mutations are common, strengthening the idea of the heterogeneous genetic background of FCCTX ( 94 , 99 ).…”

Section: From Single Genes To the Exome And Genomementioning

confidence: 97%

From APC to the genetics of hereditary and familial colon cancer syndromes

Olkinuora

Peltomäki

Aaltonen

et al. 2021

Human Molecular Genetics

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Hereditary colorectal cancer syndromes attributable to high penetrance mutations represent 9–26% of young-onset colorectal cancer cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of colorectal cancer susceptibility. With the emergence of next generation sequencing and associated methods, several predisposition loci have been unravelled but validation is incomplete. Individuals with cancer predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how colorectal cancer predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.

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Section: From Single Genes To the Exome And Genomementioning

confidence: 97%

From APC to the genetics of hereditary and familial colon cancer syndromes

Olkinuora

Peltomäki

Aaltonen

et al. 2021

Human Molecular Genetics

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“…This gene is a serine–threonine kinase receptor involving the TGF‐β signaling pathway which is a vital regulator of different cellular processes (such as cell proliferation, cell differentiation, and migration). Germline variants in BMPR1A are associated with juvenile polyposis syndrome, MMR‐proficient YOCRC, and unexplained adenomatous polyposis 64 . We identified one patient with a LP variant in BMPR1A and with an MMR‐proficient tumor.…”

Section: Discussionmentioning

confidence: 92%

Survey of germline variants in cancer‐associated genes in young adults with colorectal cancer

Mikaeel

Young

et al. 2021

Genes Chromosomes & Cancer

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Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole‐exome sequencing data of blood‐derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent a comprehensive analysis of 133 cancer‐predisposition/implicated genes. All patient tumors were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (aged 16–54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer‐predisposing gene: dMMR genes (6), MUTYH [bi‐allelic (2), mono‐allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1), and BRIP1 (1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono‐allelic) (1), ERCC4 (mono‐allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumors. Eighteen (14%) reported a first‐degree relative with CRC, but only three of these carried P/LP variants. Three patients with variants in polyposis‐associated genes showed no polyposis (one each in MUTYH [bi‐allelic], RNF43, and BMPR1A). Approximately one in five young adults in our series carried at least one P/LP variant in a cancer‐predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction; therefore multigene panel testing and genetic counseling are warranted for all young adults with CRC regardless of those two factors.

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“…However, it is unclear whether accumulated SBSs promote aging and progressive neurodegenerative diseases as evidenced by the phenotype of MMRdeficient people. MMR-deficiency neither acerates aging nor cause neurodegenerative diseases although the number of newly generated SBSs per division increases nearly 100 times (Peltomäki et al, 2020). Thus, it is an issue of future study to clarify whether a few times increase in the number of SBSs (Table 2) causes neurodegenerative symptom in NER-deficient CS an d XP patients (Lodato et al, 2018).…”

Section: Unsolved Questions and Future Prospectmentioning

confidence: 95%

“…4A, B), are embryonic lethal and die immediately after birth, respectively (Gu et al, 1994;Ludwig et al, 1998).The severe phenotype of BER-deficient animals contrasts with humans deficient in NER and MMR, who develop normally. MMR defects cause carcinogenesis in the colon epithelium in humans due to the accumulation of point mutations and changes in the copy number of STRs during DNA replication (see "Replication errors") (Peltomäki et al, 2020). If excision repair fails to remove base damage before DNA replication, error-prone TLS past damaged template strands converts DNA damage to mutations (see "Spontaneously occurring DSBs in non-dividing cells and during DNA replication" and Fig.…”

Section: Excision Repairmentioning

confidence: 99%

Nature of spontaneously arising single base substitutions in normal cells

Takeda

Luan

2021

GENOME INSTAB. DIS.

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Next-generation sequencing (NGS) of single cells and micro-dissected tissues has demonstrated that the number of somatic mutations in normal cells increases linearly with age. The majority of somatic mutations are single base substitutions (SBSs). NGS has revealed the mutagenic effect of various metabolic and environmental genotoxic agents on different cells, such as normal colonic epithelial cells, hematopoietic cells, hepatocytes, and neurons. NGS has also uncovered the clonal expansion of cells in normal tissues of the elderly driven by oncogenic mutations. There are two main mechanisms for the generation of mutations, namely, replication errors and DNA damage, with both being followed by inaccurate repair. NGS studies of normal tissues highlight the substantial contribution of the latter mechanism by revealing the significant accumulation of somatic mutations in mitotically inactive hepatocytes and neurons. This review describes the nature of spontaneously arising SBSs in normal tissues, the causes of mutagenesis, cellular pathways of the DNA damage response that suppress mutagenesis, as well as unsolved questions on the matter. KeywordsSpontaneous mutagenesis • Error-reduced NGS technology • Replication errors • Inaccurate repair of DNA damage • de novo mutation * Shunichi Takeda

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Updates in the field of hereditary nonpolyposis colorectal cancer

Cited by 20 publications

References 137 publications

From APC to the genetics of hereditary and familial colon cancer syndromes

From APC to the genetics of hereditary and familial colon cancer syndromes

Survey of germline variants in cancer‐associated genes in young adults with colorectal cancer

Nature of spontaneously arising single base substitutions in normal cells

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