Germline<i>MLH1</i>and<i>MSH2</i>mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing

Papp, J.; Kovacs, Marietta Eva; Olàh, Edith

doi:10.3748/wjg.v13.i19.2727

Cited by 35 publications

(29 citation statements)

References 33 publications

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“…Indeed, an abnormal signal was detected in MLPA analysis in one case in which no germline CDH1 mutations had been detected by sequencing analysis. Therefore, similar to the detection of genomic rearrangements in the MLH1 and MSH2 genes, which has been proposed to be included in genetic testing for Lynch syndrome, (30) we propose that screening for germline large rearrangements of CDH1 should be included in CDH1 genetic testing for FGC in the Japanese population. Aggregation (%) * * * Fig.…”

Section: Discussionmentioning

confidence: 96%

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population

et al. 2011

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Germline point or small frameshift mutations of the CDH1 (E‐cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1‐bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation‐dependent probe amplification (MLPA) and RT‐PCR analyses, we also found a large genomic deletion (c.164‐?_387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell–cell adhesion was detected in CHO‐K1 cells expressing Ile405fsX12‐ and Gly55fsX38‐type CDH1 compared with cells expressing wild‐type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC. (Cancer Sci 2011; 102: 1782–1788)

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Section: Discussionmentioning

confidence: 96%

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population

et al. 2011

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“…The aim of our group is to fill the gap, since there are very few published data from Hungary [21,[24][25][26][27][28]. Our institution has screened close to 1,500 patients to date and found 11 previously known pathogenic mutations and numerous unclassified variants.…”

Section: Discussionmentioning

confidence: 99%

Q48P mutation in the hMLH1 gene associated with Lynch syndrome in three Hungarian families

et al. 2012

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Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC) is an inherited disease with variable phenotype causing the development of colon cancer and other malignancies. The basis of the disease is believed to be the mismatch repair gene mutations. Genetic screening has been performed among the patients who have undergone surgery for colon cancer at the University of Debrecen, Department of Surgery. Tumor samples of the screened patients were submitted to immunohistochemistry on hMLH1, hMSH2 and hMSH6 genes, microsatellite instability testing, followed by sequencing and multiple ligation dependent probe amplification. Three families were identified with the missense mutation c.143A>C (p.Q48P) of hMLH1 gene. In one of the families a segregation analysis of this particular variant was also accomplished. The segregation analysis revealed a clear correlation between the tumor cases and the occurrence of this mutation. However, none of the analyzed 100 healthy controls demonstrated the same aberration. There is only one published evidence in the literature about the presence of this rare variant in any population. The Gln to Pro switch in the ATPase domain, a conservative region of the hMLH1 gene, creates significant changes in the protein structure. These results indicate that this mutation is the abnormality responsible for the patients' phenotype and it is feasible that this particular aberration occurs more frequently among Hungarian Lynch syndrome patients.

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“…El diagnóstico de los cánceres por inestabilidad de microsatélites se obtiene por el análisis genético de las mutaciones terminales 5,6 , o por el estudio de microsatélites, analizando las inserciones o delecciones del ADN tumoral 21 . Si bien estas técnicas son las más exactas, su mayor complejidad, menor disponibilidad y elevado coste, han propiciado el estudio inmunohistoquímico de la expresión tisular de las proteínas reparadoras: MLH1, MSH2, MSH6 y PMS2 como el método de aproximación para el estudio de los tumores por inestabilidad de microsatélites 8,12,22,23 .…”

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“…Estas lesiones se denominan "tumores por inestabilidad de microsatélites" y suponen el 15% de los cán-ceres colorrectales esporádicos y el 95% de los cánceres colorrectales hereditarios no polipoideos o síndrome de Lynch 3,4 . Las alteraciones del mecanismo de reparación que caracteriza a los cánceres con inestabilidad de microsatélites pueden diagnosticarse mediante el estudio genético de las mutaciones germinales 5,6 , por análisis de microsatélites 7 o por técnicas inmunohistoquímicas de expresión de las proteínas reparadoras 8 . En su conjunto, el cáncer colorrectal sigue presentando unas importantes tasas de mortalidad, que en nuestra comunidad, suponen el 10,5% del número total de fallecidos por cáncer en varones y el 14,7% en las mujeres 9 .…”

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Expresión tisular de proteínas reparadoras e infiltración linfocítica tumoral: significado pronóstico en el carcinoma colorrectal resecado

Borda

Martínez-Peñuela

Borda

et al. 2012

Anales Sis San Navarra

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Fundamento. En el cáncer colorrectal se discute la posible relación entre la expresión patológica de proteínas reparadoras (EPPR) y la infiltración linfocítica tumoral (ILT), así como el posible efecto pronóstico de ambos factores. Material y métodos.Se han revisado 243 cánceres colorrectales, resecados consecutivamente. Estudiamos inmunohistoquímicamente la EPPR de MLH1, MSH2 y MSH6. La ITL se valoró mediante la tinción de CD3 en el epitelio tumoral. Comparamos la mortalidad y progresión tumoral post-operatoria entre los casos con y sin EPPR y con y sin ITL. Adicionalmente estudiamos la mortalidad y progresión tumoral entre los casos EPPR (+), según presentaran o no ITL. conclusiones. No se ha encontrado relación entre EPPR e ITL, con tasas muy similares de ILT (+) entre casos con y sin EPPR. La ILT (+) mostró un efecto pronóstico favorable superior a la EPPR (+). La combinación de ILT (+) e EPPR (+) parece tener un efecto protector acumulativo, aunque su escasa frecuencia resta significación al hallazgo.Palabras clave. Neoplasias colorrectales. Histopatología. Inmunohistoquímica. Pronóstico.Microsatélites. aBstractBackground. In colorectal cancer there is discussion about the possible relation between the mismatch repair protein expression (MMRPE) and tumour lymphocytic infiltration (TLI), as well as the possible prognostic effect of both factors. Methods.A review was made of 243 colorectal cancers, consecutively resected. We made an immunohystochemical study of the MMRPE of MLH1, MSH2 and MSH6. The TLI was evaluated through CD3 staining in the tumoural epithelium. We compared mortality and post-operative tumoural progression amongst the cases with and without MMRPE and with and without TLI. Additionally, we studied mortality and tumoural progression amongst MMRPE (+) cases, according to whether or not they presented TLI. conclusions. No relation was found between MMRPE and TLI, with very similar rates of TLI (+) between cases with and without MMRPE. The TLI (+) showed a favourable prognostic effect higher than that of the MMRPE (+). The combination of TLI (+) and MMRPE (+) seems to have an accumulative protective effect, although its limited frequency reduces the significance of the finding.

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GermlineMLH1andMSH2mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing

Cited by 35 publications

References 33 publications

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population

Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population

Q48P mutation in the hMLH1 gene associated with Lynch syndrome in three Hungarian families

Expresión tisular de proteínas reparadoras e infiltración linfocítica tumoral: significado pronóstico en el carcinoma colorrectal resecado

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