Hotspot oncomutations: implications for personalized cancer treatment

Myers, Meagan B.; Wang, Yiying; McKim, Karen L.; Parsons, Barbara L.

doi:10.1586/erm.12.51

Cited by 13 publications

(9 citation statements)

References 142 publications

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“…Cancer hotspot mutations carry valuable information for diagnosis, prognosis and treatment [ 47 ]. In this cohort, total 10 mutations were found to be recurrently mutated in >1% patients accounting for 55.7% somatic mutations in AKT1 , PIK3CA and TP53 ( Table 4 ).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and spectrum of AKT1, PIK3CA, PTEN and TP53 somatic mutations in Chinese breast cancer patients

Guo

Chen

et al. 2018

PLoS ONE

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Breast cancer, one of the most frequently occurring cancers worldwide, is the leading cause of cancer-related death among women. AKT1, PIK3CA, PTEN and TP53 mutations were common observed in breast cancer representing potential clinical biomarkers for cancer classification and treatment. A comprehensive knowledge of AKT1, PIK3CA, PTEN and TP53 mutations in breast cancer was still insufficient in Chinese population. In this study, the complete coding regions and exon-intron boundaries of AKT1, PIK3CA, PTEN and TP53 genes were sequenced in paired breast tumor and normal tissues from 313 Chinese breast cancer patients using microfluidic PCR-based target enrichment and next-generation sequencing technology. Total 120 somatic mutations were identified in 190 of the 313 patients (60.7%), with the mutation frequency of AKT1 as 3.2%, PIK3CA as 36.4%, PTEN as 4.8%, and TP53 as 33.9%. Among these mutations, 1 in PIK3CA (p.I69N), 3 in PTEN (p.K62X, c.635-12_636delTTAACCATGCAGAT and p.N340IfsTer4) and 5 in TP53 (p.Q136AfsTer5, p.K139_P142del, p.Y234dup, p.V274LfsTer31 and p.N310TfsTer35) were novel. Notably, PIK3CA somatic mutations were significantly associated with ER-positive or PR-positive tumors. TP53 somatic mutations were significantly associated with ER-negative, PR-negative, HER2-positive, BRCA1 mutation, Ki67 high expression and basal-like tumors. Our findings provided a comprehensive mutation profiling of AKT1, PIK3CA, PTEN and TP53 genes in Chinese breast cancer patients, which have potential implications in clinical management.

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Section: Discussionmentioning

confidence: 99%

Prevalence and spectrum of AKT1, PIK3CA, PTEN and TP53 somatic mutations in Chinese breast cancer patients

Guo

Chen

et al. 2018

PLoS ONE

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“…Codon 12 is recognized as the “hotspot mutation region” having inherent instability and predisposition to single nucleotide substitutions (Myers et al 2012) with the result that majority of KRAS mutations occurs at this locus (Okudela et al 2010). It cannot be excluded that after one point mutation this region remains instable and prone to the occurrence of successive mutations.…”

Section: Discussionmentioning

confidence: 99%

Intratumor heterogeneity and tissue distribution of KRAS mutation in non-small cell lung cancer: implications for detection of mutated KRAS oncogene in exhaled breath condensate

Kordiak

Szemraj

Grabska-Kobylecka

et al. 2018

J Cancer Res Clin Oncol

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PurposeMutated KRAS oncogene in exhaled breath condensate (EBC) can be a genetic marker of non-small cell lung cancer (NSCLC). However, a possibility of inhomogeneous distribution in cancer tissue and intratumor heterogeneity of KRAS mutation may decrease its significance. We investigated a status of KRAS point mutation and its sequence at codon 12 in 51 NSCLC patients after tumor resection. The comparison of KRAS mutation status between EBC–DNA and cancer tissue was performed in 19 cases.MethodsFive cancer tissue samples from disparate tumor regions and one from normal lung were harvested at surgery. EBC was collected for DNA analysis the previous day. KRAS point mutations at codon 12 were detected using mutant-enriched PCR technique and pyrosequenced.ResultsForty-six cancers revealed concordance of KRAS mutation status: 27 contained mutated KRAS and 19 had only wild KRAS. Five NSCLCs revealed inhomogeneous distribution of KRAS mutation. Two different mutations were found in 14 NSCLCs and the most frequent one was G12D and G12V (n = 8). No mutated KRAS was found in normal lung. The concordance ratios of KRAS sequence in codon 12 between EBC–DNA and cancer were 18/19 for NSCLC patients and 11/12 for KRAS mutation positive NSCLC.ConclusionsIntratumor heterogeneity and inhomogeneous distribution of KRAS point mutation in codon 12 in cancer tissue can occur in NSCLCs. There was a high accordance between KRAS mutation status in EBC–DNA and cancer tissue in NSCLC patients what suggests usefulness of monitoring KRAS mutation in EBC–DNA as a biomarker of NSCLC.

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“…180, 181 Smoking has also been shown to be a strong risk factor for synchronous primary colorectal cancers (R Nishihara et al, unpublished data) and synchronous multiple polyps, 182 especially serrated polyps, 183 which are recognized as precursors for colorectal cancers with CpG island methylator phenotype, microsatellite instability and/or BRAF mutation. 159, 184–186 CpG island methylator phenotype-high, microsatellite instability-high and BRAF mutation can co-occur in colorectal cancer, 9, 30, 113, 184, 187–195 and are common characteristics of synchronous colorectal cancers. 67–70 Furthermore, synchronous primary colorectal cancers are considered to arise due to some form of predisposition, likely involving both genetic and environmental factors.…”

Section: The Genesis Of the “Etiologic Field Effect”mentioning

confidence: 99%

Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression

et al. 2015

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The term “field effect” (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, “etiologic field effect”, which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a “field of susceptibility” to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically-focused approach to field effect can: 1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; 2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, 3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying “etiologic field effect” as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an “etiologic field effect” paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine.

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Hotspot oncomutations: implications for personalized cancer treatment

Cited by 13 publications

References 142 publications

Prevalence and spectrum of AKT1, PIK3CA, PTEN and TP53 somatic mutations in Chinese breast cancer patients

Prevalence and spectrum of AKT1, PIK3CA, PTEN and TP53 somatic mutations in Chinese breast cancer patients

Intratumor heterogeneity and tissue distribution of KRAS mutation in non-small cell lung cancer: implications for detection of mutated KRAS oncogene in exhaled breath condensate

Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression

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