Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: analysis of loss of heterozygosity

To compare chromosomal alterations in ductal carcinoma in situ (DCIS) of different histopathological grades and to study aberrations between primary DCIS and corresponding ipsi- or contralateral new in situ or invasive tumours, a study was undertaken of the pattern of loss of heterozygosity (LOH) at chromosomal regions in which LOH has previously been described in invasive breast cancer. LOH was analysed using 19 microsatellite markers located on chromosomes 3p, 6q, 8p, 8q, 9p, 11p, 11q, 16q, 17p, and 17q in 30 women with a primary DCIS. Eleven women with DCIS of grade 1 and 19 with grade 3 according to the EORTC classification system were included. In six patients LOH was also analysed in a subsequent new breast cancer. Fractional allelic loss (FAL, the ratio of chromosomal arms where allelic loss was detected divided by the total number of chromosomal arms with informative markers) was statistically significantly higher in grade 1 DCIS compared with grade 3 (p=0.02) for the 19 loci, indicating that the amount of allelic loss does not correlate with increasing aggressiveness of the studied tumours. Also observed was a complete heterogeneity of LOH in the primary DCIS and their corresponding new events, suggesting that these events probably developed from genetically divergent clones.     

Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer

Papilloma and papillary hyperplasia (PH) have been proposed to be the putative precursor lesions of papillary transitional-cell carcinoma of the urinary bladder. We examined 15 PH lesions and 4 papillomas for loss of heterozygosity (LOH) at 17 microsatellite markers on 9 chromosomal arms. Eight of 15 (53%) PHs were clonal, demonstrating LOH of at least 1 microsatellite marker. In contrast, none of the papillomas showed any genetic changes among the markers tested. In PH, chromosomal arm 9q was the most frequently lost (4/15), followed by 9p and 18q (n = 2) and, less frequently, 8p, 10q, 11p and 17p (n = 1). Furthermore, 2 hyperplastic lesions demonstrated LOH at 9q only, confirming the notion that allelic loss on chromosomal arm 9q is among the earliest events in bladder-cancer progression. In 1 patient, identical LOH patterns were observed between PH and a recurrent transitional-cell carcinoma. Our molecular data demonstrate that at least a proportion of PHs represent pre-cancerous lesions of the bladder that subsequently progress to papillary bladder cancer. Moreover, chromosomal arm 9q may harbor a tumor-suppressor gene(s) inactivated in the earliest stages of human bladder tumorigenesis.     

Correlation of allelic losses and clinicopathological factors in primary breast cancers

Human breast cancers frequently show allelic loss or loss of heterozygosity (LOH) at specific chromosomal regions. To understand the possible role of these genetic alterations in tumor development and progression, we examined LOH at loci on chromosomal arms lp, 3p, 11p, 13q, 16q, 18q, and 22q in 140 to 246 cases of primary breast cancers and compared it with lymph node metastasis, histological type, tumor stage, estrogen receptor (ER) and progesterone receptor (PgR) status. LOH at 1_p22-31 correlated with lymph node metastasis and a tumor size of greater than 2 cm. LOH at 13ql2-14 and 18q21 were most frequently observed in tumors of the solid-tubular type. LOH at 1p34-36 was more frequent in tumors of the scirrhous and solidtubular types than in other less aggressive histological types. Furthermore, a significant association was observed between LOH at 3pl4-21, 11p11-15 and 13ql2-14 and the absence of progesterone receptors. These results suggest that some clinical characteristics of breast cancers are determined by loss of tumor suppressor genes present at specific chromosomal regions.     

Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis

Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations, and allelic imbalance throughout the genome. Loss of heterozygosity (LOH) is a common form of allelic imbalance, and the detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to characterize different tumor types, pathological stages and progression. Global patterns of LOH can be discerned by allelotyping of tumors with polymorphic genetic markers. Microsatellites are reliable genetic markers for studying LOH, but typically only a modest number of microsatellites are tested in LOH studies because the genotyping procedure can be laborious. Here we describe the use of a new alternative approach to comprehensive allelotyping in which samples are genotyped for nearly 1500 single-nucleotide polymorphism (SNP) loci distributed across all human autosomal arms. We examined the pattern of allelic imbalance in human transitional cell carcinomas of the urinary bladder including 36 primary tumors and 1 recurrent tumor with matched normal DNAs. The call rate for all SNPs was 78.5 +/- 1.87% overall samples. Overall, the median number of allelic imbalance was 47.5, ranging from 20 to 118. The mean number of allelic imbalances was 36.58, 51.30, and 67.78 for pT(a), pT(1), and > or =pT(2), respectively, and also increased by grade. The SNP microarray analysis result was validated by comparison with microsatellite allelotype analysis of 118 markers in the same tumors. Overall, the two methods produced consistent loss patterns at informative loci. The SNP assay discovered previously undiscovered allelic imbalances at chromosomal arms 12q, 16p, 1p, and 2q. The detection of LOH and other chromosomal changes using large numbers of SNP markers should enable rapid and accurate identification of allelic imbalance patterns that will facilitate the mapping and identification of important cancer genes. Moreover, SNP analysis raises the possibility of individual tumor genome-wide allelotyping with potential prognostic and diagnostic applications.     

A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution

Cancers that arise from astrocytes in the adult CNS present as either anaplastic astrocytomas (AAs) or as more aggressive glioblastomas multiforme (GBMs). GBMs either form de novo or progress from AAs. We proposed to examine the molecular genetic relationship between these CNS tumors by conducting a genome-wide allelic imbalance analysis that included 70 loci on examples of AA and GBM. We found significant loss of heterozygosity (LOH) at 13 discrete chromosomal loci in both AAs and GBMs. Loss was significant in both AAs and GBMs at 9 of these loci. AAs show the highest rates of LOH at chromosomes 1p, 4q, 6p, 9p, 11p, 11q, 13q, 14q, 15p, 17p, 17q, and 19q. GBMs showed the greatest losses at 1p, 6q, 8p, 9p, 10p, 10q, 11p, 13q, 17p, 17q, 18p, 18q, and 19q. GBMs also demonstrated significant amplification at the epidermal growth factor receptor locus (7p12). These data suggest that there are three classes of loci involved in glioma evolution. First are loci that are likely involved in early events in the evolution of both AAs and GBMs. The second class consists of AA-specific loci, typified by higher LOH frequency than observed in GBMs (4q, 6p, 17p, 17q, 19q). The third class consists of GBM-specific loci (6q, 8p, 10, 18q). Damage at these loci may either lead to de novo GBMs or permit existing AAs to progress to GBMs. Glioma-related LOH profiles may have prognostic implications that could lead to better diagnosis and treatment of brain cancer patients.     

Deletion mapping of chromosome 4q in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) frequently shows a loss of heterozygosity (LOH) on chromosome 4q. In order to define the commonly affected region on chromosome 4q for further positional cloning of the putative tumor suppressor gene, we carried out allelic imbalance (AI) studies in 41 HCCs using a panel of 43 microsatellite markers. Thirty-four cases (82.9%) showed AI at one or more loci. Detailed deletion mapping identified 7 independent, frequently deleted regions on this chromosome arm. These were the (1) D4S1615 locus, (2) D4S1598 locus, (3) D4S620 locus, (4) D4S1566 and D4S2979 loci, (5) D4S1617 and D4S1545 loci, (6)D4S1537 locus; and (7) from the D4S2920 to D4S2954 locus. Among these 7 frequently deleted regions, 5 were associated with tumor differentiation. Our results suggest that several putative tumor suppressor genes may be present on chromosome 4q and that the AI of chromosome 4q may play a role in the aggressive progression of HCC. Int. J. Cancer (Pred. Oncol.) 79:356–360, 1998. © 1998 Wiley-Liss, Inc.     

Role of chromosomal loss in the progression of prostate cancers

Cytogenetic, molecular cytogenetic, and molecular studies of prostate cancer have produced a large volume of data about chromosomal loci that are aberrant in prostate cancer. The cumulative data on prostate cancer reveal allelic losses on chromosome arms 2q, 3p, 5q, 6q, 7q, 8p, 9p, 10p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 17q, 18q, and 21q, but there is a great deal of variability between studies. In most cases, the frequency of allelic loss is higher in metastatic tissues or hormone-refractory tumors than in primary tumors. There also seem to be discrepancies in the genetic findings depending on methods employed. Molecular genetic studies, using polymerase chain reaction (PCR) analysis of microsatellite markers, demonstrated allelic loss at 7q31.1, whereas fluorescence in situ hybridization analysis showed a gain at the same region. Com-mon sites of allelic loss that are consistently observed by various methods seem to exist on chromosome arms 8p, 10q, 13q, and 16q. PTEN/MMAC1 has been identified on 10q23.3 and was found to be frequently mutated in advanced prostate cancer. Other regions are also considered to harbor genes associated with the development and progression of prostate cancer, and these could be included in the diagnostic methods for the substaging of prostate cancer. Received: September 22, 2000     

Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.

Neuroblastomas have been characterized genetically by N-myc amplification and by deletions or loss of heterozygosity (LOH) for the short arm of chromosome 1. However, recent studies have suggested deletion or allelic loss involving at least three other chromosome arms, 11q, 14q, and 17p. Therefore, we undertook an analysis of allelic loss for these respective chromosomal arms to determine the frequency and pattern of LOH as well as the correlation of these findings with other biological and clinical variables. A group of 24 pairs of normal and tumor DNAs was chosen that were representative of patients of different ages and stages. A substantial frequency of LOH (greater than or equal to 20%) was found only for 1p and 14q, whereas LOH for the other chromosome arms occurred in less than or equal to 5% of cases. On the basis of these results, we extended the analysis to a total of 59 neuroblastomas, and we found 1p LOH in 15 of the 59 cases (25%) and 14q LOH in 10 of 43 informative cases (23%). N-myc amplification was found in 15 of the 59 cases (25%). This analysis confirmed that 1p LOH and 14q LOH occurred almost exclusively in patients with advanced stages of disease. Furthermore, LOH for 1p and 14q usually occurred independent of each other, and 1p LOH frequently was associated with N-myc amplification, whereas 14q LOH was not. Thus, our results demonstrate that neuroblastomas are complex genetically and that there are at least two distinct loci for putative suppressor genes that are deleted independently in this tumor, both of which are associated with advanced stages of disease.     

Different pattern of loss of heterozygosity among endocervical-type adenocarcinoma, endometrioid-type adenocarcinoma and adenoma malignum of the uterine cervix

It is unclear which chromosome arms frequently show loss of heterozygosity (LOH) in adenocarcinoma of the uterine cervix. To identify such chromosomal arms, LOH on 52 different chromosome loci was examined using laser capture microdissection and PCR-LOH analysis in 25 common-type adenocarcinomas, comprising 13 cases of endocervical type, 12 cases of endometrioid type and 7 cases of adenoma malignum without the component of conventional endocervical-type adenocarcinoma (designated as "pure" form). In adenocarcinomas of endocervical type and endometrioid type, LOH was commonly detected on chromosome arms 17p (62% and 50%, respectively), 1p (33% and 67%) and 22q (40% and 33%). In addition, endocervical-type adenocarcinoma frequently (> or = 30%) showed LOH on 18p (71%), 19q (50%), 19p (38%) and 16q (38%), whereas endometrioid-type adenocarcinoma frequently showed LOH on 10q (43%) and 5q (40%). LOH was only sporadically detected on 9q, 18q, or 21q in 3 of 7 cases of "pure" adenoma malignum. In a case of coexistence of "pure" adenoma malignum and adenocarcinoma in situ (AIS), LOH on 1q, 5p, 11p, 17p, 18p and 18q was detected only in AIS. LOH was accumulated on a number of chromosome arms in the adenocarcinoma at the early developmental stage before stromal invasion. Chromosomal arms that are prone to show LOH appeared to differ between the 2 types of cervical adenocarcinoma. We could suggest that "pure" adenoma malignum is of clonal and neoplastic nature in view of the detection of LOH.     

Novel regions of allelic imbalance identified by genome-wide analysis of neuroblastoma

Several nonrandom chromosomal abnormalities have been associated with neuroblastoma (NB). However, the relationship of each genetic event to the clinical course of disease is not firmly established. We have performed a genome-wide allelic scan of NB to identify regions with frequent allelic imbalance (AI) and correlate the allelotype with clinical features of disease. Nineteen tumors from patients across the spectrum of NB were used. Genome-wide allelotype was performed using 169 fluorescently labeled microsatellite markers from the Weber 9a human screening set (Research Genetics, Huntsville, AL) and 48 independent markers for high-density analysis of selected regions. Eleven chromosomal regions had AI in >25% of tumors including loci known previously to be frequently altered such as 1p36 (10 of 19; 52%), 2p (9 of 19; 47%), 17q (8 of 19; 42%), 11q23 (8 of 19; 42%), 14q32 (7 of 19; 37%), 19q (6 of 19; 31%), 7q (6 of 19; 31%), 9p21 (5 of 19; 26%), and three novel regions of frequent AI at 10p11-p15 (7 of 19; 40%), 12q24.1 (5 of 19; 26%), and 8qcen-q24 (5 of 19; 26%). AI of four regions (8q, 10p, 19q, and 12q) allowed the distinction of two genetic groups that matched clinical significant subgroups of NB. AI at 12q24 and 19q13 was found exclusively in high-risk local-regional tumors, whereas AI at 10p11 and 8q appeared to be specific for stage 4 tumors with MCYN amplification. Spontaneously remitting or quiescent tumors were intact at all of the regions described above.     

Loss of heterozygosity on chromosome 16p and 18q in anaplastic thyroid carcinoma

The aim of this study was to clarify the genetic alterations in anaplastic transformation of the thyroid cancer. A total of 17 thyroid cancers including 7 anaplastic and 10 papillary cancers were analyzed for loss of heterozygosity (LOH) on chromosome 16p and 18q. All the samples from anaplastic cancer showed LOH at one or more loci out of ten markers on 16p, and only two showed one LOH at two loci out of five markers on 18q. No LOH was found on either 16p or 18q in papillary cancers. D16S423, D16S418 and D16s406 on 16p13.3 were the most frequently deleted loci in anaplastic cancers, and the region around these may harbor the putative tumor suppressor gene related to anaplastic transformation of thyroid cancer.     

Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer

Dilution end point loss of heterozygosity (LOH) analysis, a novel approach for the analysis of LOH, was used to evaluate allelic losses with the use of 21 highly polymorphic microsatellite markers at nine chromosomal sites most frequently affected in smoking-related non-small cell lung cancers. Allelotyping was done for bronchial epithelial cells and matching blood samples from 23 former and current smokers and six nonsmokers as well as in 33 adenocarcinomas and 25 squamous cell carcinomas (SCC) and corresponding matching blood from smokers. Major conclusions from these studies are as follows: (a) LOH at chromosomal sites 8p, 9p, 11q, and 13q (P >0.05, Fisher's exact test) are targeted at the early stages, whereas LOH at 1p, 5q, 17p, and 18q (P <0.05, Fisher's exact test) occur at the later stages of non-small cell lung cancer progression; (b) LOH at 1p, 3p, 5q, 8p, 9p, 11q, 13q, 17p, and 18q occurs in over 45% of the tobacco smokers with SCC and adenocarcinoma; (c) compared with bronchial epithelial cells from smokers, there is a significantly higher degree of LOH at 1p, 5q, and 18q in adenocarcinoma and at 1p, 3p, and 17p in SCC (P <0.05, Fisher's exact test). We propose that lung cancer progression induced by tobacco smoke occurs in a series of target gene inactivations/activations in defined modules of a global network. The gatekeeper module consists of multiple alternate target genes, which is inclusive of but not limited to genes localized to chromosomal loci 8p, 9p, 11q, and 13q.     

Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites.

Deletions of tumour-suppressor genes can be detected by loss of heterozygosity (LOH) studies, which were performed on 23 cases of adenocarcinoma of the oesophagus, using 120 microsatellite primers covering all non-acrocentric autosomal chromosome arms. The chromosomal arms most frequently demonstrating LOH were 3p (64% of tumours), 5q (45%), 9p (52%), 11p (61%), 13q (50%), 17p (96%), 17q (55%) and 18q (70%). LOH on 3p, 9p, 13q, 17p and 18q occurred mainly within the loci of the VHL, CDKN2, Rb, TP53 and DCC tumour-suppressor genes respectively. LOH on 5q occurred at the sites of the MSH3 mismatch repair gene and the APC tumour-suppressor gene. 11p15.5 and 17q25-qter represented areas of greatest LOH on chromosomes 11p and 17q, and are putative sites of novel tumour-suppressor genes. LOH on 9p was significantly associated with LOH on 5q, and tumours demonstrating LOH at both the CDKN2 (9p21) and MSH3 (5q11-q12) genes had a significantly higher fractional allele loss than those retaining heterozygosity at these sites. Six of nine carcinomas displaying microsatellite alterations also demonstrated LOH at CDKN2, which may be associated with widespread genomic instability. Overall, there are nine sites of LOH associated with oesophageal adenocarcinoma.     

Allelotype analysis of adenocarcinoma of the gastric cardia.

To identify chromosomal loci involved in the development of proximal gastric adenocarcinoma, this study delineated the pattern of allelic imbalance in a series of 38 adenocarcinomas arising in the gastric cardia. A total of 137 microsatellite markers covering all autosomal arms, excluding acrocentric arms, were analysed. A mean of 35 out of a total of 39 chromosomal arms studied were informative for each patient. The tumour group demonstrated a high level of allelic imbalance, with an observed median fractional allelic imbalance of 0.47 for the 29 intestinal-type adenocarcinomas and 0.54 for the nine diffuse-type adenocarcinomas. Allelic imbalance was detected in >50% of informative cases in both histological subtypes on a number of chromosomal arms. In the intestinal subtype, these included, 3p (61%), 4q (71%), 5q (59%), 8p (60%), 9p (65%), 9q (83%), 12q (52%), 13q (52%), 17p (78%) and 18q (70%). A higher incidence of allelic imbalance was detected on chromosome 16q in tumours of the diffuse type relative to those of the intestinal type. A more detailed mapping on chromosomes 4q and 6q identified a number of cases with subchromosomal breakpoints. In conclusion, this analysis has indicated regions of the genome potentially involved in the development of proximal gastric carcinomas.     

A statistical analysis of chromosome 11 and 17 loss of heterozygosity in epithelial ovarian cancer

Many regions of the genome exhibit loss of heterozygosity (LOH) in epithelial ovarian cancer (EOC) suggesting sites of recessive genetic elements such as tumor suppressor genes. We performed detailed LOH studies of chromosomes 17 and 11 using 24 microsatellite repeat markers in a population of 47 patients with EOC. Univariate statistical analysis revealed that significant co-losses of chromosomal loci occurred between 17p and 17q whole arms (p=0.0003), NME1 (17q21) with D11S922 (11p15.5) (p=0.0067) and D11S912 (11q24) with D11S935 (11p13) (p=0.0073). Statistical analysis of the relationship between LOH on particular chromosomal arms and clinicopathological factors revealed a significant association between serous histological subtype of ovarian adenocarcinoma and chromosome 17p (p=0.0052) and telomeric 17q (p=0.0007) LOH. An analysis of specific polymorphic chromosomal loci demonstrated that adverse survival was significantly associated with LOH at 11q24 (p=0.0067) and 17q21 (p=0.0076). There were nonsignificant trends suggesting a relationship between chromosome 17p LOH and poorly differentiated (p=0.025) and advanced FIGO stage (p=0.031) tumours. Considering these statistical associations, a preliminary multistep model for involvement of chromosomes 11 and 17 in ovarian neoplasia can be constructed.     

Screening of selected genomic areas potentially involved in thyroid neoplasms

Loss of heterozygosity (LOH) studies have been used to identify sites harbouring tumour suppressor genes (TSGs) involved in tumour initiation or progression. To further elucidate the genetic mechanisms for follicular and papillary thyroid tumours development, we studied the frequency of LOH in 36 thyroid tumours (21 follicular thyroid adenomas (FAs) and 15 papillary thyroid carcinomas (PTCs)) on 10 specific genomic areas: 3p22, 3p25, 7q21, 7q31, 10q23, 10q25-26, 11q13, 11q23, 13q13 and 17p13.3-13.2 using 20 polymorphic markers. We have selected these areas for two reasons: (a) Even though LOH in thyroid neoplasms has been described in some of these areas, results are controversial, and (b) we have also studied areas described as involved in other epithelial or endocrine tumour types, but not studied up to now in thyroid neoplasms. Two areas showed a high percentage of LOH: 7q31 and 11q23. A 62% LOH was found at 7q31 in the FAs, suggesting, as other authors have proposed, that at least one TSG must be present in the vicinity of the c-met locus. The second area in frequency was at the 11q23 locus, with a 45% LOH in the FAs. This area was studied because it has been described as being involved in the development of epithelial and endocrine cancers. This locus had not been studied before in thyroid neoplasms. This result is interesting because the LOH11CR2A gene is localised at this locus. We suggest that this gene and/or an other TSG nearby may be involved in the progression to FA. In our study, a low percentage of LOH was found in the PTC samples, indicating that TSGs present in the areas we have studied are not significantly involved in their progression. Our data also suggest that TSGs located in areas where no LOH was detected (PTEN, MEN1, Cyclin D1, BRCA2 and RFC3) are not involved or do not have an important role in tumour progression.     

Loss of heterozygosity on chromosome 1 in human hepatoblastoma

In previous studies we have found loss of heterozygosity (LOH) on chromosome arm 11p in 33% of hepatoblastomas (HBs). In addition, cytogenetic studies have revealed aberrations of chromosome arm 1p in single cases. Therefore, we have used the PCR to amplify 10 microsatellites on the short arm and 7 microsatellites on the long arm of chromosome 1 to assess allelic loss in 32 cases of HB. LOH on chromosome 1 was found in 11 cases. Seven HBs showed LOH on chromosome 1p, 7 cases had LOH on 1q, and 3 tumors had LOH on both 1p and 1q. Six HBs with LOH on 1p had LOH at DIS243 (1p36.3), and one tumor had a loss at DIS80 maintaining heterozygosity at DIS243. A common region of overlap was present at the telomeric chromosomal portion of 1p between DIS80 and DIS243. Of the HBs with LOH on 1q, 4 showed a common region of overlap at 1q31-q32.1, and the other 3 at DIS1609 located more telomerically. The parental origin of the lost allele was of random distribution for chromosome arm 1p and of paternal origin for chromosome arm 1q. Our data suggest that tumor suppressor genes located at the telomeric region of chromosome arm 1p and different regions of chromosome arm 1q may be involved in the pathogenesis of HB. © 1996 Wiley-Liss, Inc.     

Correlation of allelic losses and clinicopathological factors in 504 primary breast cancers

BACKGROUND: We have defined 18 chromosomal regions in which allelic losses were frequent among breast cancers. We examined whether specific allelic losses might correlate with any clinicopathological factors. METHODS: We tested DNA from matched normal and tumor tissues for loss of heterozygosity (LOH) at 18 microsatellite loci from a cohort of 504 patients who had undergone surgery for breast cancer. RESULTS: LOH at 3p14.3 correlated with a larger size of tumor (greater than 2 cm). LOH at 1p22, 3p25.1, 3p14.3, or 17q21.1 correlated with loss of estrogen receptors. LOH at as many as eleven regions correlated with loss of progesterone receptor, suggesting that these represent general phenomena associated with progression of cancer. Above all, allelic losses at 11q23-24, 13q12, 17p13.3, or 22q13 significantly correlated with lymph-node metastasis (11q23-24, p= 0.0042; 13q12, p=0.0207; 17p13.3, p=0.0478; 22q13, p=0.0162). CONCLUSION: These results suggest that some clinical characteristics of breast cancers are determined by loss of tumor suppressor genes present at specific chromosome regions. Especially, LOH at 11q23-24, 13q12, 17p13.3, and 22q13 is a significant predictor of lymph-node metastasis for patients who have undergone surgery for breast cancer, and may serve as a negative prognostic indicator.     

Association of allelic loss on 1q, 4p, 7q, 9p, 9q, and 16q with postoperative death in papillary thyroid carcinoma.

Papillary thyroid carcinomas, most of which are characterized by slow growth and good prognosis, account for the majority of thyroid carcinomas. To provide appropriate postoperative management, it is important to classify them by prediction of their prognosis. To find genetic markers associated with poor prognosis, allelic loss at all 39 nonacrocentric chromosome arms was compared in 24 deceased cases and 45 age-, sex-, stage-, and type-matched survived cases. Allelic loss was examined in primary tumors from both groups using highly polymorphic microsatellite markers on 39 nonacrocentric autosomal arms. Age at diagnosis, sex, stage, and types of tumors were matched between the two groups. No recurrent tumor was used for DNA analysis. Mean fractional allelic loss in the deceased and survived cases was 0.10+/-0.08 and 0.03+/-0.05 (P < 0.001). The survived cases showed marginal frequencies of allelic loss throughout all chromosome arms except 22q. The deceased cases showed frequent allelic losses on chromosomes 1q (37%), 4p (21%), 7q (20%), 9p (36%), 9q (31%), and 16q (29%), with significant difference (P < 0.05). These chromosome regions may include tumor suppressor genes whose inactivation is associated with aggressive phenotypes of papillary thyroid carcinoma.     

Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia.

One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and nonprogressing oral premalignant lesions. However, such samples are rare, and they require long-term follow-up. The current study used the large archive network and clinical database in British Columbia to study loss of heterozygosity (LOH) in cases of early oral premalignancies, comparing those with a history of progression to carcinoma in situ or invasive cancer and those without a history of progression (referred to as nonprogressing cases). Each of 116 cases was analyzed for LOH at 19 microsatellite loci on seven chromosome arms (3p, 4q, 8p, 9p, 11q, 13q, and 17p). The progressing and nonprogressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p because virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in nonprogressing cases. Individuals with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, 11q, or 17p), which appeared uncommon in nonprogressing cases, showed 33-fold increases in relative cancer risk. In conclusion, analysis of LOH at 3p and 9p could serve as an initial screening for cancer risk of early premalignancies. Follow-up investigation for additional losses would be essential for predicting cancer progression.