Homozygous PMS2 Deletion Causes a Severe Colorectal Cancer and Multiple Adenoma Phenotype Without Extraintestinal Cancer

Olivia Will, Luis Carvajal-Carmona, Patricia Gorman, Kimberley M. Howarth, Angela M. Jones, Guadalupe M. Polanco-Echeverry, Jo Anne Chinaleong, Thomas Günther, Andrew Silver, Susan K. Clark, Ian Tomlinson

Research output: Contribution to journalArticle

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Abstract

Background & Aims: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Methods: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. Results: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or β-catenin, but KRAS2 and TGFBR2 mutations were found. Conclusions: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

Original languageEnglish (US)
Pages (from-to)527-530
Number of pages4
JournalGastroenterology
Volume132
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Adenoma
Colorectal Neoplasms
Phenotype
Mutation
Neoplasms
Immunohistochemistry
Dinucleotide Repeats
Adenomatous Polyps
Consanguinity
Catenins
Microsatellite Instability
DNA Mismatch Repair
Chromosomes, Human, Pair 7
Comparative Genomic Hybridization
Germ Cells
Brain Neoplasms
Intellectual Disability
Exons
Adenocarcinoma
Parents

ASJC Scopus subject areas

  • Gastroenterology

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Homozygous PMS2 Deletion Causes a Severe Colorectal Cancer and Multiple Adenoma Phenotype Without Extraintestinal Cancer. / Will, Olivia; Carvajal-Carmona, Luis; Gorman, Patricia; Howarth, Kimberley M.; Jones, Angela M.; Polanco-Echeverry, Guadalupe M.; Chinaleong, Jo Anne; Günther, Thomas; Silver, Andrew; Clark, Susan K.; Tomlinson, Ian.

In: Gastroenterology, Vol. 132, No. 2, 02.2007, p. 527-530.

Research output: Contribution to journalArticle

Will, O, Carvajal-Carmona, L, Gorman, P, Howarth, KM, Jones, AM, Polanco-Echeverry, GM, Chinaleong, JA, Günther, T, Silver, A, Clark, SK & Tomlinson, I 2007, 'Homozygous PMS2 Deletion Causes a Severe Colorectal Cancer and Multiple Adenoma Phenotype Without Extraintestinal Cancer', Gastroenterology, vol. 132, no. 2, pp. 527-530. https://doi.org/10.1053/j.gastro.2006.11.043
Will, Olivia ; Carvajal-Carmona, Luis ; Gorman, Patricia ; Howarth, Kimberley M. ; Jones, Angela M. ; Polanco-Echeverry, Guadalupe M. ; Chinaleong, Jo Anne ; Günther, Thomas ; Silver, Andrew ; Clark, Susan K. ; Tomlinson, Ian. / Homozygous PMS2 Deletion Causes a Severe Colorectal Cancer and Multiple Adenoma Phenotype Without Extraintestinal Cancer. In: Gastroenterology. 2007 ; Vol. 132, No. 2. pp. 527-530.
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AU - Will, Olivia

AU - Carvajal-Carmona, Luis

AU - Gorman, Patricia

AU - Howarth, Kimberley M.

AU - Jones, Angela M.

AU - Polanco-Echeverry, Guadalupe M.

AU - Chinaleong, Jo Anne

AU - Günther, Thomas

AU - Silver, Andrew

AU - Clark, Susan K.

AU - Tomlinson, Ian

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N2 - Background & Aims: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Methods: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. Results: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or β-catenin, but KRAS2 and TGFBR2 mutations were found. Conclusions: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

AB - Background & Aims: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. Methods: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. Results: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or β-catenin, but KRAS2 and TGFBR2 mutations were found. Conclusions: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.

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