Exome sequencing in diagnostic evaluation of colorectal cancer predisposition in young patients

Tanskanen, Tomas; Gylfe, Alexandra E.; Katainen, Riku; Taipale, Minna; Renkonen–Sinisalo, Laura; Mecklin∥, Jukka–Pekka; Järvinen, Heikki; Tuupanen, Sari; Kilpivaara, Outi; Vahteristo, Pia; Aaltonen, Lauri A.

doi:10.3109/00365521.2013.783102

Cited by 14 publications

(14 citation statements)

References 28 publications

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“…32 We suggest to perform MUTYH genetic testing in these unresolved MSI-H cases with additional adenomas either in the two fragments harbouring the common mutations or in the course of nextgeneration sequencing cancer kits including the MMR genes, APC and MUTYH besides others. 18 We reported for the first time a MAP patient initially suspected of LS, in which two MAP-specific somatic MSH2 mutations explained the IHC loss of MSH2/MSH6 in his MSI-H tumour. MAP might be a differential diagnosis for CRC patients with MSI-H tumours and several adenomas.…”

Section: Discussionmentioning

confidence: 82%

“…13,14 Three further MAP patients were identified with MSI-H tumours but no information on IHC for MMR proteins was given, 15,16 whereas other studies detected no biallelic MUTYH mutation carrier in patients with MSI-H tumours. [17][18][19][20] To investigate the role of MAP as a possible cause of somatic mutations in MMR genes we analysed MUTYH in blood DNA of 85 'unresolved' patients suspected of having LS due to IHC loss of MMR protein expression.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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“…A series of 157 MSI CRCs and 148 MSS CRCs were derived from a previously characterized population-based series of 1042 Finnish CRCs and an additional series of approximately 1000 unselected CRCs [9][10][11]. All tumor DNAs were extracted from histologically evaluated freshfrozen tissue.…”

Section: Study Subjectsmentioning

confidence: 99%

3′-UTR poly(T/U) repeat of EWSR1 is altered in microsatellite unstable colorectal cancer with nearly perfect sensitivity

et al. 2015

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Approximately 15% of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5%) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.

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“…Recent genomic studies have argued for an increased emphasis on global neoplastic MST changes to broaden of definition of MSI [18, 19, 27, 29, 30]. This work is the first to test somatic variability of MSTs and non-repetitive DNA sequences in colon and Hepatocellular carcinoma (LIHC) using Next-Gen sequencing.…”

Section: Introductionmentioning

confidence: 99%

Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression

Vaksman

Garner

2015

Oncotarget

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Microsatellites (MSTs) are short tandem repeated genetic motifs that comprise ~3% of the genome. MST instability (MSI), defined as acquired/lost primary alleles at a small subset of microsatellite loci (e.g. Bethesda markers), is a clinically relevant marker for colorectal cancer. However, these markers are not applicable to other types of cancers, specifically, for liver cancer which has a high mortality rate. Here we show that somatic MST variability (SMV), defined as the presence of additional, non-primary (aka minor) alleles at MST loci, is a complementary measure of MSI, and a genetic marker for colorectal and liver cancer. Re-analysis of Illumina sequenced exomes from The Cancer Genome Atlas indicates that SMV may distinguish a subpopulation of African American patients with colorectal cancer, which represents ~33% of the population in this study. Further, for liver cancer, a higher rate of SMV may be indicative of an earlier age of onset. The work presented here suggests that classical MSI should be expanded to include SMV, going beyond alterations of the primary alleles at a small number of microsatellite loci. This measure of SMV may represent a potential new diagnostic for a variety of cancers and may provide new information for colorectal cancer patients.

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Exome sequencing in diagnostic evaluation of colorectal cancer predisposition in young patients

Abstract: Microsatellite instability positivity or gastrointestinal polyposis characterized all patients with unambiguous highly penetrant germline mutations. In our series, exome sequencing produced little added value in diagnosing the underlying predisposition conditions.

Cited by 14 publications

References 28 publications

Biallelic MUTYH mutations can mimic Lynch syndrome

Biallelic MUTYH mutations can mimic Lynch syndrome

3′-UTR poly(T/U) repeat of EWSR1 is altered in microsatellite unstable colorectal cancer with nearly perfect sensitivity

Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression

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