Abstract
Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3′ end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3′ end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3′ deletions in PMS2 are not a frequent occurrence in such families.
This is a preview of subscription content, log in via an institution to check access.
References
Vaughn CP, Hart KJ, Samowitz WS, Swensen JJ (2011) Avoidance of pseudogene interference in the detection of 3′ deletions in PMS2. Hum Mutat 32:1063–1071
De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964
Nakagawa H et al (2004) Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 64:4721–4727
Senter L et al (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428
Vaughn CP et al (2010) Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum Mutat 31:588–593
Clendenning M et al (2006) Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 27:490–495
Schouten JP et al (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57
Pavlicek AR et al (2005) Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome. Genome Res 15:1487–1495
van der Klift HM et al (2010) Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. Hum Mutat 31:578–587
Newcomb PA et al (2007) Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 16:2331–2343
Lindor NM et al (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048
Vaughn CP et al (2012) The frequency of previously undetectable deletions involving 3′ exons of the PMS2 gene. Genes Chromosom Cancer 52:107–112
Clendenning M et al (2011) Mutation deep within an intron of MSH2 causes Lynch syndrome. Fam Cancer 10:297–301
van der Klift HM et al (2005) Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosom Cancer 44:123–138
Acknowledgments
The authors thank all study participants of the Colon Cancer Family Registry and study co-coordinators and technical staff for their contributions to this project, in particular Judi Maskiell, Belinda Nagler, Sally-Ann Pearson, Rhiannon Walters, David Packenas and Erika Pavluk and participant interviewers for their contributions to this project. We thank individual participants in the study who made this work possible and the contribution of the Jeremy Jass Memorial Pathology Collection. This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators. Collaborating centres include Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC], Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794), and University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). MAJ is an NHMRC Senior Research Fellow. JLH is an NHMRC Australia Fellow. During this work JY was supported by a Cancer Council Queensland Senior Research Fellowship.
Conflict of interest
The authors have no conflict of interest to declare with respect to this manuscript.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
Disclaimer
The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. Authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Clendenning, M., Walsh, M.D., Gelpi, J.B. et al. Detection of large scale 3′ deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?. Familial Cancer 12, 563–566 (2013). https://doi.org/10.1007/s10689-012-9597-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-012-9597-4