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(American Journal of Pathology. 1998;153:363-366.)
© 1998 American Society for Investigative Pathology

Short Communications

Genetic Pathways of Colorectal Carcinogenesis Rarely Involve the PTEN and LKB1 Genes Outside the Inherited Hamartoma Syndromes

Zhen-Jung Wang*{dagger} , Fleur Taylor*{ddagger} , Michael Churchman* , Gail Norbury{ddagger} and Ian Tomlinson*§

From the Tumour Genetics Group,* Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; Department of Surgery,{dagger} First Teaching Hospital, Beijing, China; NHS Molecular Genetics Laboratory,{ddagger} Churchill Hospital, Oxford, United Kingdom; and Molecular and Population Genetics Laboratory,§ Imperial Cancer Research Fund, London, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Germline mutations of the PTEN/MMAC1/TEP and LKB1 genes cause hamartomas to develop in the gastrointestinal tracts of patients with Cowden syndrome and Peutz-Jeghers syndrome, respectively. PTEN mutations may also be responsible for some cases of juvenile polyposis. Histologically, hamartomas appear benign, but there is good evidence that in these syndromes, the hamartomas can progress to colorectal carcinoma. It remains unknown whether or not cancers that develop from hamartomas acquire a spectrum of mutations similar to those in sporadic colon cancers. PTEN and LKB1 are candidate genes for mutations in sporadic colon cancers, either as initiating events in tumorigenesis or providing a selective advantage during tumor growth. Using single-strand conformational polymorphism analysis, we have screened a set of sporadic colon cancers for somatic mutations in PTEN and LKB1. No variants predicted to alter protein function were detected in LKB1, but 1 of 72 cancers showed a somatic mutation in PTEN, together with allele loss. This cancer did not have a detectable APC mutation or allele loss at APC. It remains possible that PTEN and LKB1 are inactivated in other sporadic colon cancers by means such as deletion or promoter methylation. Like BRCA1 and BRCA2, however, it appears that PTEN and LKB1 mutations can cause cancers when present in the germline, but occur rarely in the soma.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Mendelian diseases that predispose to colorectal cancer include familial adenomatous polyposis (FAP; MIM175100); hereditary nonpolyposis colon cancer (MIM120435/6); and the hamartoma syndromes Peutz-Jeghers syndrome (PJS, MIM175200), juvenile polyposis syndrome (MIM174900), and Cowden syndrome (CS, MIM158350). The genes responsible for FAP and hereditary nonpolyposis colon cancer have been shown to play important roles in the pathogenesis of sporadic cancers of the colon and of other sites. The APC gene (which is mutated in the germline of FAP patients) is involved in up to 80% of all sporadic colon cancers,1 and the mismatch repair loci (which are responsible for hereditary nonpolyposis colon cancer) are mutated or silenced in up to 10% of cancers of the colorectum and endometrium.2

CS is known as the multiple hamartoma syndrome, and individuals with this condition develop characteristic features such as cobblestone papules of the mouth and juvenile polyps of the gastrointestinal tract. CS predisposes to cancers of the thyroid, breast, and gastrointestinal tract, including the colorectum in some reported cases.3 The CS gene has been shown to be PTEN/MMAC1/TEP (10q22 to q23),4 a dual-specificity phosphatase that acts as a tumor suppressor and is mutated in several tumor types, including glioblastomas, prostate carcinoma, and a small proportion of breast cancers.5-13 Inherited PTEN mutations are also responsible for Bannayan-Zonnona syndrome (MIM153480)8,14; its features include macrocephaly, lipomas, hemangiomas, and juvenile polyps. There is conflicting evidence concerning the suggestion that germline PTEN mutations can also cause juvenile polyposis of the gastrointestinal tract in the absence of the other features of CS or Bannayan-Zonnona syndrome.15,16

PJS is another syndrome of multiple gastrointestinal hamartomas (of a histological type different from juvenile polyps), which are usually associated with characteristic freckling of the lips and buccal mucosa. PJS predisposes to cancers of multiple sites, especially the colon, breast, testis, and ovary.17 The PJS gene is LKB1 (STK11) (19p13.3), a serine/threonine kinase and a tumor suppressor.18,19

There is good evidence that the hamartomas in PJS, juvenile polyposis syndrome, and (to a lesser extent) CS can progress to colorectal carcinoma. Allele loss occurs in sporadic colon cancers close to PTEN at a frequency of about 30%20 and close to LKB1 at a frequency of about 20% (I. Tomlinson, unpublished data). Both PTEN and LKB1 are therefore good candidates for involvement in the pathogenesis of sporadic tumors of the large bowel. PTEN and/or LKB1 mutations might be selected at any stage of colorectal tumorigenesis, the most intriguing possibility being that they can initiate tumorigenesis. We have screened 72 unselected sporadic cancers of the colorectum for mutations in the PTEN and LKB1 genes to test these candidate loci for a role in colorectal tumorigenesis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Using standard methods, DNA was extracted from samples of fresh-frozen sporadic colon cancer and matched normal tissue or blood. These cases had no known family history suggestive of FAP, hereditary nonpolyposis colon cancer, or any of the hamartoma syndromes. Other standard clinicopathological data (age, grade, stage, and tumor site) were obtained from hospital records. Single-strand conformational polymorphism (SSCP) analysis was performed on the cancer samples. Published oligonucleotides and reaction conditions4-6,15 were used to amplify specifically each exon of PTEN; for some longer exons, the products of the polymerase chain reaction were then subjected to restriction endonuclease digestion to render them optimally short for mutation detection by SSCP (AluI for exons 1, 5, 6, 7, and 9 and MboI for exon 8). New oligonucleotides were designed for exon-by-exon amplification of LKB1 (Table 1) using a protocol of 94°C for 3 minutes (one time), 35 cycles of 94°C for 1 minute/annealing temperature °C for 1 minute/72°C for 1 minute, and 72°C for 5 minutes (one time). Polymerase chain reaction products were heated to 90°C for 5 minutes and subjected to electrophoresis on a 10% acrylamide gel (30:0.8 acrylamide:bisacrylamide, 10% glycerol) under nondenaturing conditions at 20 mA for about 16 hours. DNA was detected by silver staining of gels using standard methods. For all tumors with possible mutations according to SSCP analysis, that exon was reamplified in duplicate from genomic DNA in the polymerase chain reaction, and these purified polymerase chain reaction products were sequenced in forward and reverse orientations using the Applied Biosystems, Inc. (Foster City, CA) Ready Reaction Dye Terminator Cycle Sequencing kit and the 377 Prism sequencer. All sequencing reactions were performed alongside samples with wild-type genotypes and with known mutations.


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  		Table 1. Oligonucleotides Used for SSCP Analysis of LKB1

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
For LKB1, no variant band was detected in any tumor sample on SSCP analysis. Control samples from three PJS patients with known mutations showed bandshifts. For PTEN, however, a small number of bandshifts was observed in the tumor samples using SSCP analysis. Sequencing confirmed a mutation in one tumor (1.4%), resulting from a complex change at the exon 2/intron 2 boundary. This mutation altered the "wild-type" sequence GTA AGG TAAGAAT to GTA AGA GTAATGC (where exonic sequences are in regular type and intronic sequences are in italics). This results in 1) a silent AGG->AGA Arg->Arg change in codon 53, 2) substitution of the more typical donor splice site consensus sequence GTAA for the atypical wild-type sequence TAAG, and 3) a 2-bp deletion in intron 2. It is quite possible that this change affects mRNA splicing, although no source of mRNA was available to prove this contention. Exons 2 and 3 do not constitute a mode 3 number of nucleotides, and aberrant splicing would therefore be expected to lead to a truncated protein. The exon 2/intron 2 change was not present in the germline, and the patient, a 75-year-old male with Dukes' C colorectal carcinoma, had no features of CS, Bannayan-Zonnona syndrome, or juvenile polyposis syndrome. The mutation at codon 53 of PTEN has not been reported previously in the germline or soma. Previous studies demonstrated that this tumor showed allele loss close to PTEN20 and did not show a truncating mutation in exon 15 or allele loss at APC.21


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The initiating events in the pathogenesis of cancers in the hamartoma syndromes are almost certainly germline and somatic mutations at LKB1, PTEN, or related, uncharacterized genes. We have found that PTEN and LKB1 mutations in sporadic colon cancers occur at a low frequency or are absent altogether. Thus, the colon cancers in PJS and CS (and possibly some cases of juvenile polyposis syndrome) follow genetic pathways that are distinct from the majority of colorectal tumors (at least regarding their initiating events). Other workers have found APC mutations in juvenile polyps with dysplasia,22 showing that there is partial overlap between the genetic pathways of tumorigenesis in hamartoma syndromes, FAP, and sporadic colon cancers.

Given the reported moderate sensitivity of SSCP of about 80%,23-25 especially for detecting point mutations, we cannot exclude the possibility that mutations at PTEN or LKB1 occur in a somewhat higher proportion of colon cancers than reported here. It is noteworthy, however, that the spectra of germline and somatic mutations in PTEN and of germline mutations in PJS include small deletions that would be easily detected using SSCP analysis 4,5,8,12,19,26 ; in addition, SSCP analysis in our study detected positive control samples in both genes that resulted from point mutations. The previously unreported PTEN mutation that we detected was accompanied by allele loss and, although its effect at the protein level cannot be proven, we suspect that this mutation was selected for a role in tumorigenesis. Colon cancer may thus resemble carcinoma of the breast, in which somatic PTEN mutations occur in a small but important subset of tumors.

Further possibilities for the involvement of PTEN or LKB1 that we have not excluded are gene silencing by promoter methylation or hemi- or homozygous deletion of either locus (whether the entire gene or whole exons). The latter possibility would be consistent with the observed allele loss close to PTEN and LKB1 in colon cancers, and homozygous deletions have been observed at PTEN in a variety of tumors.5 It remains entirely possible, however, that the allele loss close to PTEN and/or LKB1 in colon cancers targets different loci in both cases.

There is, in general, a far from perfect association between the spectrum of tumors in Mendelian cancer syndromes and the range of sporadic tumors in which the same gene is mutated. The familial breast/ovarian cancer genes, BRCA1 and BRCA2, for example, cause cancer when mutant in the germline, but are hardly ever mutated in sporadic cancers. There is, however, evidence that BRCA1 is inactivated by promoter methylation in some sporadic breast cancers,27 thus suggesting that defective BRCA1 can provide a selective advantage to breast tumors whether derived from the germline or soma, albeit through different mechanisms. There will be great potential interest in studying the expression of PTEN and LKB1 mRNA in colorectal tumors and in screening for mutations of LKB1 in sporadic tumors of other sites.


   Acknowledgements
 
We are very grateful to Charis Eng and Ian Frayling for assistance with PTEN mutation detection protocols and to Lauri Aaltonen for information regarding LKB1. Latch Ilyas provided useful comments on the manuscript.


   Footnotes
 
Address reprint requests to Dr. Ian Tomlinson, Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. E-mail: iptomlin{at}hgmp.mrc.ac.uk

Supported in part by a grant from the Cancer Research Campaign. Z-JW is supported by the Chinese Government. IT is supported by the Jane Ashley Trust.

Zhen-Jung Wang and Fleur Taylor contributed equally to this work.

Accepted for publication May 6, 1998.


   References
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 References
 

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