Genomic alterations in human breast carcinomas

All human chromosomes were screened in 52 human breast carcinomas for the occurrence of allele losses, in order to identify genomic alterations involved in initiation and progression of the disease. Loss of chromosome 22 alleles was detected in 6 out of 8 lobular carcinomas, while chromosome 17 losses were most frequent in ductal carcinomas. Furthermore, patients who developed advanced disease after many years of mild clinical course showed significantly higher frequencies of allele losses in their primary tumors, compared to patients with a persistently mild disease course. Finally, in one case, molecular examination suggested a translocation t(10;17) with coamplification of the ERBB2 oncogene and chromosome 10 sequences present in the two tumors from this patient, consistent with one of the tumors being a metastasis originating from a subclone of cells in the other tumor.     

Genomic alterations in salivary gland carcinomas: an illustrated update

Since the publication of our review on genomic alterations in salivary gland tumours in Diagnostic Histopathology in 2020, there have been several major developments. In the United Kingdom, next generation sequencing (NGS) of several tumour types is now commissioned by the National Health Service (NHS) either by whole genome sequencing (WGS) of fresh tumours, or targeted NGS in formalin-fixed paraffin embedded (FFPE) tissue. The UK genomic test directory includes several key gene fusion tests in salivary tumours, including NTRK, MAML2, EWSR1 and MYB. These can aid the clinician not only in refining histopathological classification in challenging cases, but they also have important therapeutic implications for patients with recurrent disease or where standard-of-care management options have been exhausted. This review will provide a brief update, including newly described entities since the previous review (most notably microsecretory carcinoma), as well as illustrating the utility of genomic testing in salivary tumours using several recent examples from our clinical practice.     

Genomic aberrations in mucinous tubular and spindle cell renal cell carcinomas.

Mucinous tubular and spindle cell carcinoma of the kidney is a new diagnostic entity. We present the pathologic and genomic characteristics of three such low-malignant tumors. Two of the tumors were found in women aged 19 and 52 years, the third tumor was found in an 80-year-old man, and the tumor stages were pT2N0MX, pT2NXMX, and pT1NXMX, respectively. Findings by immunohistochemistry were similar but not identical for the three cases; markers for both proximal and distal parts of the nephron were expressed in each tumor, a finding that is in agreement with data from previous studies. The Ki-67-labeling index was below 5 in all three cases. Two of the tumors were predominantly hypodiploid (DNA-indexes 0.77 and 0.80), whereas the third tumor was hypertriploid (1.57) as measured by DNA-image cytometry. From the latter tumor live cells were available making it possible to establish its karyotype: 62-70,XXX,+del(X)(q11),-1,+2,+4,-5,-6,+7,-8,-9,-10,-11,+12,-13,-14,-15,+16,+17,+18,-19,+20,+21,-22[cp15]. Interphase fluorescence in situ hybridization analyses with centromere-specific probes for chromosomes 1, 3, 4, 6, 7, 9, 10, 17, 18, 20, and X showed that the two hypodiploid tumors had disomic and monosomic chromosome populations, whereas the karyotyped, near-triploid tumor was dominated by trisomic chromosome populations. Comparative genomic hybridization analysis was normal for the karyotyped tumor but abnormal for the two others. We conclude that multiple numerical chromosome aberrations may be a feature of mucinous tubular and spindle cell carcinomas of the kidney, but beyond that no clear-cut karyotypic aberration pattern is so far discernible.     

Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast

Pure invasive micropapillary carcinoma (MPC) is a special histological type that accounts for 0.7-3% of all breast cancers. MPC has a distinctive growth pattern and a more aggressive clinical behaviour than invasive ductal carcinomas of no special type (IDC-NSTs). To define the molecular characteristics of MPCs, we profiled a series of 12 MPCs and 24 grade and oestrogen receptor (ER)-matched IDC-NSTs using high-resolution microarray comparative genomic hybridization (aCGH). In addition, we generated a tissue microarray containing a series of 24 MPCs and performed immunohistochemical analysis with ER, PR, Ki-67, HER2, CK5/6, CK14, CK17, EGFR, topoisomerase-IIalpha, cyclin D1, caveolin-1, E-cadherin, and beta-catenin antibodies. In situ hybridization probes were employed to evaluate the prevalence of amplification of HER2, TOP2A, EGFR, CCND1, MYC, ESR1, and FGFR1 genes. aCGH analysis demonstrated that MPCs significantly differed from IDC-NSTs at the genomic level. Gains of 1q, 2q, 4p, 6p, 6q23.2-q27, 7p, 7q, 8p, 8q, 9p, 10p, 11q, 12p, 12q, 16p, 17p, 17q, 19p, 20p, 20q, and 21q, and losses of 1p, 2p, 6q11.1-q16.3, 6q21-q22.1, 9p, 11p, 15q, and 19q were more prevalent in MPCs. High-level gains/amplifications of 8p12-p11, 8q12, 8q13, 8q21, 8q23, 8q24, 17q21, 17q23, and 20q13 were significantly associated with MPCs. A comparison between 24 MPCs and a series of 48 grade and ER-matched IDC-NSTs revealed that high cyclin D1 expression, high proliferation rates, and MYC (8q24) amplification were significantly associated with MPCs. Our results demonstrate that MPCs have distinct histological features and molecular genetic profiles supporting the contention that they constitute a distinct pathological entity.     

mdm2 gene alterations and mdm2 protein expression in breast carcinomas

This study investigates the mdm2 gene status and expression in 66 surgically resected human breast carcinomas, with correlations with clinico-pathological and biological data (histological type, grading, steroid receptor status, p53 expression, proliferative activity). Four (7.7 per cent) out of 52 informative cases bear mdm2 gene amplification (four- to ten-fold) and 8 (15.4 per cent) of 52 cases showed borderline amplification (three-fold). Nine (13.6 per cent) out of 66 cases showed strong mdm2 nuclear immunoreactivity. Twenty-seven (40.9 per cent) cases showed isolated mdm2 reactive nuclei. All cases with clear amplification showed a high percentage of mdm2 immunoreactive nuclei. The relationship between gene amplification and mdm2 protein expression is highly significant (P<0.0001). No association was observed between mdm2 gene amplification and any of the considered clinico-pathological and biological parameters, while mdm2 immunoreactivity showed a significant association only with oestrogen receptor immunoreactivity (P=0.009). p53 expression was associated neither with mdm2 gene amplification nor with mdm2 immunoreactivity. It could be tempting to hypothesize that the evaluation of the combined mdm2/p53 immunohistochemical phenotype in human breast carcinoma could give us better prognostic information than the evaluation of the expression of the p53 protein alone.     

Expression of cathepsin D and galectin 3 in tubular carcinomas of the breast

Tubular carcinoma (TC) is a distinctive type of grade I (G1) ductal carcinoma with particularly favourable outcome and low rate of axillary metastases. To the best of our knowledge, few data are available in the literature concerning the expression of molecules mediating intercellular and cell-matrix interactions in TC. We examined with immunohistochemical methods the expression of galectin 3 and cathepsin D in 17 TC and in 33, 31 and 28 ductal carcinomas of G1, grade II (G2) and grade III (G3), respectively. Results were compared using Chi-square test. Galectin 3 expression was higher in TC than in G1 carcinomas (p<0.05). The pattern of immunostaining was also different with a focal cytoplasmic apical reinforcement in TC. However, cathepsin D stromal and epithelial expression was similar in TC and G1 cases (p>0.05), and lower than in G2 and G3 patients at a stromal level. The higher expression of galectin 3 in TC and its focal staining (apical) pattern suggests that within the group of G1 carcinomas, galectin 3 expression varies according to histological type, and may correlate with prognosis and metastatic potential. We also suggest that cathepsin D could not be involved in neoplastic progression and metastasis in low-grade (G1) ductal breast carcinomas.     

Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas

Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas
Aims : The aim of this work is the study of the prognostic significance of the chromosomal aberrations described in a series of invasive ductal breast carcinomas.
Methods and results : We analysed by comparative genomic hybridization a group of 70 formalin-fixed paraffin-embedded invasive ductal breast carcinomas. Aberrations showed a frequency similar to previous studies using frozen tumours. Interestingly, we identified gains involving 6q16-q24 more frequently than in other series. We analysed the association among the chromosomal imbalances, 11 histopathological factors, relapse rate and overall survival of patients. Associations showed 16q losses as a potential marker of good prognosis, as they were more frequent in node-negative ( P =0.025) and in oestrogen-positive tumours ( P  < 0.001). Furthermore, 100% of bcl-2+ tumours presented this aberration compared with 29.3% in bcl-2– ( P =0.014). 1q, 11q, 17q and 20q gains were associated with poor prognosis: 95% of cases with 1q gains were bigger than 20 mm ( P =0.041). Tumours with 1q and 11q gains showed a higher relapse rate ( P =0.063; P =0.066). Within the good prognosis group of lymph node-negative patients, 17q and 20q gains identify a subgroup with increased relapse rate ( P =0.039).
Conclusions : Chromosomal imbalances, together with histopathological factors, may help to predict outcome in breast cancer patients.     

Absence of microsatellite instability in breast carcinomas with both p53 and c-erbB-2 alterations

Based on a previous finding that amplification of the c-erbB-2 oncogene and alteration of p53 are strongly associated in most aggressive breast tumours, the present study investigated whether microsatellite instability (MI) might also be associated with this tumour phenotype. Nine polymorphic microsatellite markers, including six dinucleotide, one trinucleotide, and two tetranucleotide repeats, were amplified from paired normal and tumour DNA samples of 15 breast tumours that overexpressed both c-erbB-2 and p53 and of 15 control breast tumours that overexpressed neither protein. All 30 breast tumours analysed exhibited a replication error-negative phenotype, with only one sample showing MI in one of the nine loci. This suggests that the genetic events underlying MI, which are critical in colorectal and gastric tumours, are not involved in the pathogenesis of c-erbB-2/p53 double-altered breast tumours and do not play a central role in breast tumour formation. Copyright © 1999 John Wiley & Sons, Ltd.     

Radial scars of the breast and breast carcinomas have similar alterations in expression of factors involved in vascular stroma formation

We recently reported that radial scars are an independent histologic risk factor for breast cancer. The reason for this association is not known. Given the importance of stromal-epithelial interactions in the pathogenesis of breast cancer, we studied radial scars for the expression of a number of factors known to be involved in the formation of vascular stroma in breast cancer. In situ hybridization was performed on formalin-fixed paraffin sections using (35)S-labeled riboprobes for collagen type 1, total fibronectin, extra domain A (ED-A)+ fibronectin, thrombospondin 1, vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF), and one of its endothelial receptors, kinase insert domain-containing receptor (KDR) (vascular endothelial growth factor receptor [VEGFR-2]). Expression levels in radial scars (9 cases) were compared with those in normal breast tissue (15 cases) and infiltrating ductal breast carcinoma (4 cases). Factor VIII-related antigen immunostaining was used to define the distribution of microvessels in radial scars, carcinoma, and normal breast tissue. Compared with normal breast tissue, the radial scars showed focally increased numbers of blood vessels and focally increased expression of messenger RNA (mRNA) for collagen type 1, total fibronectin, ED-A+ fibronectin, thrombospondin 1, VPF/VEGF, and KDR. This pattern of mRNA overexpression was similar to that seen in the 4 invasive cancers. We conclude that there are similarities between radial scars and invasive breast cancers with regard to the level of mRNA expression for several factors involved in the formation of vascular stroma. These results suggest that a similar disturbance in stromal-epithelial interactions is present in both lesions.     

Genomic aberrations in carcinomas of the uterine corpus

Endometrial carcinoma, the most common invasive neoplasm of the female genital tract, occurs either in a hormone-related, less virulent form (type I) or in a hormone-independent, more aggressive form (type II). Another cancer of the uterine corpus is carcinosarcoma, a biphasic or mixed epithelial-mesenchymal tumor, now classified as metaplastic carcinoma. We examined by karyotyping and comparative genomic hybridization a consecutive series of 67 endometrial carcinomas and 15 carcinosarcomas and compared the cytogenetic features of the different carcinoma subtypes. All three subtypes of uterine carcinoma had in common a nonrandom gain of material from 1q and 8q but differed from one another in other respects. Endometrial carcinomas of type I mostly presented gains from chromosome arms 1q and 8q and losses from Xp, 9p, 9q, 17p, 19p, and 19q, whereas endometrial carcinomas of type II showed a more complex imbalance picture, with gains from chromosome arms 1q, 2p, 3q, 5p, 6p, 7p, 8q, 10q, and 20q and losses from Xq, 5q, and 17p. The carcinosarcomas mostly showed gains of or from 1q, 5p, 8q, and 12q but losses from 9q, that is, they were much more similar to endometrial carcinomas in their pattern of acquired genomic changes than to sarcomas of the uterine corpus. It was also possible to identify different copy number changes among the different grades of type I carcinomas, between serous papillary and clear-cell carcinomas of type II, as well as between homologous and heterologous carcinosarcomas. Specifically, type I adenocarcinomas that were highly differentiated mostly showed gains from 1q and 10p; those that were moderately differentiated showed gains from 1q, 7p, 7q, and 10q as well as losses from Xp, 9p, 9q, 17p, 19p, and 19q; whereas those poorly differentiated showed gains from 1q, 2p, 2q, 3q, 6p, 8q, and 20q but losses from Xp, Xq, 5q, 9p, 9q, 17p, and 17q. The serous papillary carcinomas showed gains from 1q, 2p, 2q, 3q, 5p, 6p, 6q, 7p, 8q, 18q, 20p, and 20q but losses from 17p, whereas the clear-cell carcinomas showed gains from 3q, 7p, 8q, 10q, 16p, and 20q but losses from 6q. Finally, the homologous carcinosarcomas presented gains from 1p, 1q, 8q, 12q, and 17q as well as losses from 9q and 13q, whereas the heterologous tumors showed gains from 1q, 8p, and 8q. The reproducibility of the observed correlations between karyotypic aberration patterns and histological differentiation was underscored by the fact that those carcinosarcomas whose epithelial component resembled type I endometrial carcinomas also exhibiting a type I aberration profile, whereas carcinosarcomas with a type II carcinoma differentiation had karyotypic abnormalities similar to those of type II endometrial carcinomas.     

Chromosome alterations in 21 non-small cell lung carcinomas

Cytogenetic analysis was performed on 16 primary tumors, 2 effusions, and 3 cell lines from 21 patients with non-small cell lung cancer (NSCLC). In 20 patients specimens were obtained prior to initiating cytotoxic therapy. Extensive clonal chromosome alterations were found in all cases. The most frequent numerical changes were polysomy 7 and polysomy 20 (each seen in 12 specimens). In addition, tumor cells from another six cases exhibited partial trisomy 7, with the shortest region of overlap (SRO) at 7p11-p13. Rearrangements of chromosomes 1, 3, 6, 8, 11, 15, 17, and 19 were each observed in nine or more tumors. Breakpoints were clustered at several chromosomal sites, including 1p13, 3p13, 15p11-q11, 17p11, and 19q13. Recurrent loss involving 1p, 3p, 6q, 11p, 15p, 17p, and 19q were each seen in at least eight cases. The SRO of 3p losses was at band 3p21. Double minute chromosomes were found in three tumors. Overall, our findings indicate that even though karyotypes in newly diagnosed NSCLC are very complex, recurrent cytogenetic changes can be identified. The high incidence of loss of 17p (14 of 21 specimens) appears to be compatible with reports implicating the TP53 gene (at band 17p13) as a frequent site for genetic alteration in lung cancer. Moreover, the recurrence of loss of 3p (12 cases) and 11p (10 cases) is also consistent with recent molecular evidence. The existence of other "hot spots" for cytogenetic change, particularly those involving specific regions on chromosomes 7, 15, and 19, warrants further molecular investigation of these sites in NSCLC.     

Chromosomal alterations in paired gastric adenomas and carcinomas

Gastric adenoma is a precancerous lesion of the stomach and its malignant transformation is thought to result from accumulative series of gene alterations. The aim of this study was to determine the pattern of chromosomal changes during gastric carcinogenesis. Pairs of adenoma and carcinoma tissues from 15 gastrectomy cases containing both adenomas and carcinomas in the same (adjacent pairs, 6 cases) and different (non-adjacent pairs, 9 cases) lesions, were analyzed for chromosomal alterations of 39 non-acrocentric chromosomal arms by comparative genomic hybridization (CGH). CGH analysis identified frequent chromosomal alterations in most of the gastric adenomas (14/15, 93%) and all of the carcinomas. The mean number of chromosomal alterations was higher in carcinoma (5.5 for adenoma and 11.7 for carcinoma; P = 0.006, by nonparametric Wilcoxon's test). Losses on the short arm of chromosome 17 were most common in both adenomas (43%) and carcinomas (67%). The pattern of chromosomal alterations in paired gastric adenomas and carcinomas showed greater similarity compared to the non-case pairs and this similarity was increased in the adjacent pairs. Deletion mapping analysis on chromosome 17p also demonstrated that the conserved deletion area was more frequent in the adjacent pairs. Among these 6 adjacent pairs, all had common deletion areas. In contrast, among the 9 non-adjacent pairs, 2 (22%) had common area of deletion, 5 (56%) showed deletion only in the carcinoma, and the remaining 2 (22%) had no deletion on 17p, suggesting diverse genetic changes might be involved in the multiple tumor formation. Our results that common clonal genetic changes between adjacent pairs of gastric adenomas and carcinomas and accumulated genetic changes in the carcinomas provide evidences for the stepwise mode of gastric carcinogenesis through the accumulation of a series of genetic alterations.     

Vimentin expression in breast carcinomas

Epithelial malignancies expressing mesenchymal markers and their prognostic implications have been studied by various authors. In view of this, we studied fifty cases of breast carcinomas for vimentin expression and correlated the various clinical and histopathological parameters. Eighteen percent (9/50) of all breast carcinomas expressed vimentin. Vimentin positive tumours were predominantly larger in size (mean greatest diameter 5.43 cm), of higher TNM stage, node negative (55.56%), poorly differentiated (66.66%, p=0.0458) with high mitotic rate (>10/hpf, p=0.0000), Estrogen (88.88%) and Progesterone (77.77%) receptor negative thus pointing towards aggressive biological behavior. Interestingly 20% of well differentiated and 9.09% of moderately differentiated tumours also expressed vimentin. One vimentin positive case had pulmonary metastases despite being node negative while another well differentiated vimentin positive tumour showed skeletal muscle infiltration. Hence, we conclude that vimentin expression is an indicator of biologically aggressive tumours.     

Synaptophysin in human breast carcinomas

Synaptophysin expression was studied immunohistochemically in 109 female and in three male breast carcinomas. Positivity was demonstrated in 10 female and in two male tumours in a high percentage of neoplastic cells. Synaptophysin positive breast carcinomas also expressed other neuroendocrine markers such as chromogranin and neuron-specific enolase.     

Glutamate-L-cysteine ligase in breast carcinomas

Aims : To investigate the immunohistochemical expression of the catalytic and regulatory subunits of γ-glutamyl cysteine synthetase, i.e. glutamate-L-cysteine ligase (GLCL) in 274 invasive and in-situ breast carcinomas. GLCL is the rate-limiting enzyme in glutathione synthesis, which is one of the most important intracellular antioxidants participating in the detoxification reactions of several cytotoxic drugs.
Methods and results : In the tumour cells GLCL reactivity was observed in 50% and 44% of the cases for the catalytic and the regulatory subunits, respectively. There was a statistically significant association between their expression ( P =  0.002). Lobular invasive carcinomas expressed the catalytic and regulatory subunits more often than other tumours ( P =  0.050 and P  = 0.046, respectively). Also in-situ carcinomas expressed the catalytic subunit more often ( P = 0.005). Tumours showing no immunoreactivity for the catalytic subunit had axillary metastases significantly more often ( P =  0.013). Patients with tumours showing positivity for either subunit or both had a better survival ( P =  0.037). No difference in survival could be observed between GCLC-positive or -negative cases in the subgroup receiving chemotherapy.
Conclusions : Expression of the catalytic and regulatory subunits of GLCL is found in a substantial number of breast carcinomas and their expression is more pronounced in lobular invasive and in-situ carcinomas. Even though the overall expression of GLCL was associated with improved survival, no such effect was observed separately in the group receiving chemotherapy.     

Genetic alterations in breast cancer

The etiology of breast cancer involves a complex interplay of various factors, including genetic alterations. Many studies have been devoted to the identification and characterization of mutations that occur frequently during breast tumorigenesis. The major types of genetic abnormalities that are frequently observed in breast tumors are amplification of protooncogenes (MYC, ERBB2) and DNA from chromosome band 11q13; mutation of TP53; and loss of heterozygosity from chromosomes and chromosome arms 1, 3p, 6q, 7q, 8p, 11, 13q, 16q, 17, 18q, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, linkage analyses of large families with a predisposition to breast cancer have been performed in order to map breast cancer susceptibility genes (TP53, BRCA1, BRCA2). The findings have thrown light on the molecular mechanisms of breast cancer and have enabled various genetic markers to be used in clinical oncology.     

Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferationin the breast

The identification of genomic alterations occurring in neoplastic lesions provides insight into both lesion occurrence and disease progression. In this study, we used microarray comparative genomic hybridization (CGH) to investigate genetic changes in atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), as the presence of these lobular neoplastic lesions is an indicator of risk in the development of invasive breast cancer. DNA was extracted from microdissected archival breast tissue containing ALH or LCIS, lacking adjacent invasive carcinoma, and subjected to whole-genome tiling path microarray-CGH using the submegabase resolution tiling set (SMRT)-array platform. Twelve ALH and 13 LCIS lesions were examined. Copy number alterations were identified using statistical criteria and validated with Real-Time PCR and fluorescence in situ hybridization. From statistical analysis, a greater number of alterations were observed in ALH compared to LCIS. Alterations common to ALH include gain at 2p11.2 and loss at 7p11-p11.1 and 22q11.1. Alterations common to LCIS include gain at 20q13.13 and loss at 19q13.2-q13.31. In both ALH and LCIS, we observed loss of 16q21-q23.1, an altered region previously identified in lobular neoplasia and invasive carcinoma. The validation of select alterations reinforces the genomic signature. This study represents the first whole-genome investigation of lobular neoplastic breast lesions using clinical archival specimens. The identified genomic signature includes copy number alterations not previously identified for lobular neoplasia. This genomic signature, common to ALH and LCIS, suggests a role for the acquisition of novel genomic alterations in the aberrant cellular proliferation that defines lobular neoplasia.     

Genetic alterations in breast cancer

The development of neoplasms is the result of the accumulation of genetic alterations. In breast cancer, large efforts have been dedicated to unravel these genetic alterations and to find associations between specific genetic alterations and the clinical and pathological characteristics of the tumour. There has been rapid advancement of the available techniques to identify new genetic alterations; technical advancement will also place the detection of genetic alterations in breast carcinomas within the grasp of routine clinical testing. As tumour behaviour is largely determined by these genetic alterations, it is to be expected that clinical decision-making in the future will be increasingly influenced by knowledge of the genetic make-up of a tumour. In breast cancer, the main genetic alterations are amplification of approximately 10 oncogenes and inactivation of an unknown number of tumour suppressor genes. In addition, germline mutations in the BRCA1 and 2 genes account for genetic predisposition to develop breast and ovarian cancer. The histological tumour type has been shown to be associated with the presence of specific genetic alterations: for example, inactivation of E-cadherin is specific for the development of lobular breast cancer; HER2 (c-erb B2) gene amplification is associated with poorly differentiated ductal cancer; and tumours in patients with BRCA1 and 2 germline mutations are often poorly differentiated ductal cancers. Also, associations between specific genetic alterations and clinical behaviour (i.e. metastating potential and sensitivity to systemic treatment) are starting to emerge.     

Genomic instability occurs in colorectal carcinomas but not in adenomas

Genomic instability, as demonstrated by the presence of additional alleles at short tandemly repeated (STR) loci, has recently been observed in colorectal tumours from individuals with hereditary non-polyposis colorectal cancer (HNPCC), and in some sporadic tumours. These neoplasms have been called replication error positive (RER⁺). In this study, we confirm the presence of genomic instability in a proportion of unselected colorectal carcinomas but find no evidence of instability in adenomas. We further report replication errors in a tetranucleotide sequence, and in STRs within two tumour suppressor genes. 108 colorectal adenocarcinomas and 46 adenomas were analysed for the presence of variant bands at 4–15 microsatellite markers. Seven (6.5%) of carcinomas were RER⁺, four of which originated from the proximal colon. Analysis of the adenomas and of matched adenoma-carcinoma and carcinoma-metastatic samples from four patients suggests that the replication errors may occur during the development of carcinomas but are rare in adenomas. © 1993 Wiley-Liss, Inc.