• Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic

• Clinical characteristics of Taiwanese hereditary non-polyposis colorectal cancer kindreds.

• Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite

• Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability.

• Cancer genetics and their application to individualised medicine.

• Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary

• A novel germline mutation of hMLH1 in a patient with hereditary non-polyposis colorectal cancer.

• [Risk factors for the development of ovarian carcinoma]

1
UI - 11854177
AU - Zhou XP; Kuismanen S; Nystrom-Lahti M; Peltomaki P; Eng C
TI - Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors.
SO - Hum Mol Genet 2002 Feb 15;11(4):445-50
AD - Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. To determine whether PTEN is involved in the pathogenesis of EC arising in HNPCC cases, and whether PTEN inactivation precedes MMR deficiency, we obtained 41 ECs from 29 MLH1 or MSH2 mutation positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28/41) of the HNPCC-related ECs with absent or weak PTEN expression. The remaining 27% (11/41) of tumors had normal expression and 5% (2/41) with mixed populations showing weak/absent as well as normal expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. These results suggest that PTEN plays a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. Furthermore, we have shown that somatic PTEN mutation, especially frameshift, is a consequence of profound MMR deficiency in HNPCC-related ECs. In contrast, among 60 previously reported MSI+ sporadic ECs with 70 somatic mutations in PTEN, 39 (56%) were frameshift, of which only eight (21%) were affecting the 6(A) tracts in exon 7 or 8 (P = 0.01), suggesting that PTEN mutations may precede MMR deficiency.

2
UI - 12051017
AU - Wei SC; Wang MH; Shieh MC; Wang CY; Wong JM
TI - Clinical characteristics of Taiwanese hereditary non-polyposis colorectal cancer kindreds.
SO - J Formos Med Assoc 2002 Mar;101(3):206-9
AD - Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.
BACKGROUND AND PURPOSE: The prevalence of colorectal cancer in Taiwan has increased gradually in recent years. Around 5% to 15% of colorectal cancer is hereditary, and hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. This study aimed to determine the clinical characteristics of Taiwanese HNPCC kindreds. PATIENTS AND METHODS: We reviewed the chart records of all HNPCC kindreds followed-up in our hospital during the period from 1996 to 1999. Their clinical characteristics were recorded and analyzed. RESULTS: There were 10 families, including a total of 202 persons, who met the Amsterdam criteria for HNPCC. Fifty-two persons in these families had a diagnosis of cancer, including 26 women and 26 men. There were 40 colorectal cancers, five endometrial cancers, five gastric cancers, two ovarian cancers, two hepatocellular carcinomas, and one each of lung cancer, breast cancer, thyroid cancer, and pancreatic cancer (six patients had two cancers). The mean age at cancer diagnosis was 42.1 years. Among the 12 occurrences in 11 colorectal cancer patients with complete clinical and pathological findings, most cancers (67%) were located proximal to the splenic flexure (right-side colon). One patient had metachronous colorectal cancer. CONCLUSIONS: This is the first report of the general clinical characteristics of Taiwanese HNPCC. The clinical characteristics of HNPCC in Taiwan were similar to those in Western countries. The genetic bases of Taiwanese HNPCC patients remain to be determined.

3
UI - 12057899
AU - Kuismanen SA; Moisio AL; Schweizer P; Truninger K; Salovaara R; Arola J;
TI - Butzow R; Jiricny J; Nystrom-Lahti M; Peltomaki P Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability.
SO - Am J Pathol 2002 Jun;160(6):1953-8
AD - Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.

4
UI - 11978509
AU - Jass JR; Walsh MD; Barker M; Simms LA; Young J; Leggett BA
TI - Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability.
SO - Eur J Cancer 2002 May;38(7):858-66
AD - Department of Pathology, University of Queensland, Herston, Queensland 4006, Australia. j.jass@mailbox.uq.edu.au
Attempts to classify colorectal cancer into subtypes based upon molecular characterisation are overshadowed by the classical stepwise model in which the adenoma-carcinoma sequence serves as the morphological counterpart. Clarity is achieved when cancers showing DNA microsatellite instability (MSI) are distinguished as sporadic MSI-low (MSI-L), sporadic MSI-high (MSI-H) and hereditary non-polyposis colorectal cancer (HNPCC). Divergence of the 'methylator' pathway into MSI-L and MSI-H is at least partly determined by the respective silencing of MGMT and hMLH1. Multiple differences can be demonstrated between sporadic and familial (HNPCC) MSI-H colorectal cancer with respect to early mechanisms, evolution, molecular characterisation, demographics and morphology. By acknowledging the existence of multiple pathways, rapid advances in the fields of basic and translational research will occur and this will lead to improved strategies for the prevention, early detection and treatment of colorectal cancer.

5
UI - 11978511
AU - Liefers GJ; Tollenaar RA
TI - Cancer genetics and their application to individualised medicine.
SO - Eur J Cancer 2002 May;38(7):872-9
AD - Department of Surgery, K6R, Leiden University Medical Center, Leiden, The Netherlands. gjwillemijn@mindless.com
One of the great challenges of basic research is to translate scientific discoveries into the improved treatment of patients. For colorectal cancer, our increased understanding of the molecular aetiology of the disease has not yet been paralleled by an improvement in patient care. However, several new approaches are on the verge of clinical implementation. Technical advances such as real-time polymerase chain reaction (PCR) and microarray techniques coupled to insight in the molecular pathways in colorectal cancer makes it possible to develop new clinical tools for the diagnosis, classification and treatment of patients. The ultimate goal of the incorporation of cancer genetics into the clinical treatment of patients is individualised medicine; therapeutic strategies based on the molecular taxonomy of tumours and individually constructed for each patient.

6
UI - 12067992
AU - Wahlberg SS; Schmeits J; Thomas G; Loda M; Garber J; Syngal S; Kolodner
TI - RD; Fox E Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families.
SO - Cancer Res 2002 Jun 15;62(12):3485-92
AD - Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Forty-eight hereditary nonpolyposis colorectal carcinoma (HNPCC) families for which a tumor sample was available were evaluated for the presence of germ-line mutations in MSH2 and MLH1, tumor microsatellite instability (MSI), and where possible, expression of MSH2 and MLH1 in tumors by immunohistochemistry. Fourteen of 48 of the families had a germ-line mutation in either MSH2 or MLH1 that could be detected by genomic DNA sequencing, and 28 of 48 of the families had MSI-H tumors. Four additional families showed loss of expression of MSH2, and one additional family showed loss of expression of MLH1 but did not have germ-line mutations in MSH2 or MLH1 that could be detected by DNA sequencing. MSI-H, as defined using the National Cancer Institute recommended five-microsatellite panel, had a 100% sensitivity for identifying samples having MSH2 or MLH1 mutations or loss of expression. In contrast, loss of MSH2 and MLH1 expression did not identify all samples having germ-line mutations in MSH2 or MLH1, because in five cases, a mutant protein product was expressed that could be detected by IHC. A combination of the Bethesda criteria for HNPCC and an MSI-H phenotype defined the smallest number of cases having all of the germ-line MSH2 and MLH1 mutations that could be detected by DNA sequencing.

7
UI - 12110639
AU - Gonda K; Nomizu T; Fukayama N; Sugano K; Takenosita S
TI - A novel germline mutation of hMLH1 in a patient with hereditary non-polyposis colorectal cancer.
SO - Jpn J Clin Oncol 2002 Jun;32(6):215-8
AD - Department of Surgery, Hoshi General Hospital, Koriyama, Fukushima, Japan. nomizu@hoshipital.or.jp
DNA mismatch repair genes, hMLH1 and hMSH2, assigned on chromosome 3p21-23 and 2p21-22 are involved in hereditary non-polyposis colorectal cancer (HNPCC). The heterozygous carrier of the mutated allele results in a mutator phenotype and accelerating tumorigenesis, which especially causes carcinomas in the gastrointestinal and genitourinary tracts. We screened germline mutations of mismatch repair genes hMLH1 and hMSH2 in a patient with multiple primary neoplasms (multiple stomach cancers, colon cancer and brain tumor) in a cancer clustered HNPCC family. Screening by long RT-PCR from the RNA extracted from puromycin-treated heparinized blood showed skipping of the exon 2 in hMLH1. The analysis of the genomic DNA showed a GT deletion in the splice-donor site of the exon 2, which is compatible with the splicing variant detected by long RT-PCR analysis. This is a novel germline mutation that has not been reported previously.

8
UI - 11965725
AU - Malinova M
TI - [Risk factors for the development of ovarian carcinoma]
SO - Akush Ginekol (Sofiia) 1999;38(1):57-60

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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