Earlier onset and multiple primaries in familial as opposed to sporadic esophageal cancer

AIM: To study the differences in onset age and multiple primary cancers between familial and sporadic esophageal squamous cell carcinoma (ESCC). METHODS: The differences in onset age and multiple primary cancers were analyzed between ESCC patients with (n = 766) and without (n = 1776) a family history of the cancer. The cases analyzed constituted all consecutive patients who had undergone cure-intent surgery at the Department of Thoracic Surgery of the 4^th Hospital of Hebei Medical University from January 1 1975 to December 31 1989. Because we also originally aimed to examine the difference in survival time, only older subjects with a long follow-up period were selected. RESULTS: Overall, patients with ESCC and a positive family history of the cancer had a significantly younger age at onset and more multiple primary cancers than those without a positive family history (51.83 ± 8.39 vs 53.49 ± 8.23 years old, P = 0.000; 5.50% vs 1.70%, P = 0.000). Both of these differences were evident in subgroup analyses, however, no correlations were observed. While age at onset differed significantly by family history in males, smokers, and drinkers, the difference in multiple primary cancers by family history was significant in nonsmoking, nondrinking, and younger onset patients. In multivariate analysis, age over 50 years, tobacco smoking, and multiple primary cancers were found to be significant predictors of familial cancer: the corresponding OR (95%CI) and P-value were 0.974 (0.963-0.985) and 0.000; 1.271 (1.053-1.535) and 0.012; and 4.265 (2.535-7.176) and 0.000, respectively. CONCLUSION: Patients with ESCC and a positive family history of the cancer had a significantly younger onset age and more multiple primary cancers than those without a positive family history. Sub-group analyses indicated that younger onset age may be due to the interaction of genetic predisposition and environmental hazards, and multiple primary cancers may only be due to genetic predisposition.     

Clinicopathological analysis on cancers of autopsy cases in a geriatric hospital

It is generally accepted that cancers in the eiderly are of low grade mallgnancy. In order to clarify this point, autopsy cases from a medical center for the elderly between 1982 and 1994 were pathologlcally analyzed. Three hundred and fifty (160 males, 190 females) out of a total of 871 (361 males, 510 females) autopsy cases were examined. The Incidence of cancer In varlous age groups were found to be as follows: <69 years, 24/67 (36%); 70–74 years, 401102 (39%); 75–79 years, 54/136 (39%); 80–84 years, 79/180 (44%); 85–89 years, 66/172 (38%); 90–94 years, 59/137 (43%); 95–99 years, 17/56 (30%); and >100 years, 12/21 (57%). The incidences did not significantly differ among the groups, that is, there was no age-dependency in the Incidence of cancer. Furthermore, the incidences of multiple cancers (two or more different malignancies In one patient) also did not differ. However, deaths due to the cancers showed a tendency to decrease with age. The survival periods of clinical cancer cases without a surgical operation history (time period between the date of diagnosis and death), were age-related for female cases. However, the rate of distant metastasis was not age-related. The incidence of latent cancers in individuals over 85 years of age was 79/174 (45.4%) and significantly higher than the value of 69/234 (29.5%) for those under 85. The number of malignant tumors in various organs for the different age groups was also counted and the total numbers of clinical cancers and latent cancers in each organ were, 50 and 23 in the lung, 46 and 20 in the stomach, 41 and 31 in the colon, 0 and 39 in the prostate, and 14 and 0 in the mammary glands, respectively. All prostate cancers were latent cancers, and all mammary cancers were clinical cancers. These findings provide strong evidence that cancers In individuals of advanced age have less mailgnency potential.     

Age of first cancer diagnosis and survival in Bloom syndrome

PurposeThis study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined.MethodsData from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed.ResultsAmong the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants.ConclusionWe describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.     

Microsatellite instability in early onset and familial colorectal cancer.

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.     

Gastric cancer in individuals with Li-Fraumeni syndrome

PurposeLi-Fraumeni syndrome is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. Although sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as Li-Fraumeni syndrome-associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer in Li-Fraumeni syndrome.MethodsPedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute Li-Fraumeni syndrome registry. We identified subjects with gastric cancer documented either by pathology report or death certificate and performed pathology review of the available specimens.ResultsAmong 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. Gastric cancer was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at gastric cancer diagnosis were 43 and 36 years, respectively (range: 24–74 years), significantly younger compared with the median age at diagnosis in the general population based on Surveillance Epidemiology and End Results data (71 years). Five (8.1%) families reported two or more cases of gastric cancer, and six (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.ConclusionsEarly-onset gastric cancer seems to be a component of Li-Fraumeni syndrome, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of gastric cancer.     

Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis.

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.     

Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations

Hereditary breast carcinomas constitute about 10% of all malignant mammary tumors, but the selection criteria to identify a high-risk population carrying BRCA1 mutations are not yet well-defined. We have collected 51 pedigrees of familial breast cancer, 16 pedigrees of familial breast and ovarian cancer, and 30 cases of early-onset breast cancer (<35 years of age) without any family history of breast cancer. The index cases of the 97 selected families were further subdivided into three groups based on histopathological parameters: group A (n = 19) was characterized by tumor grade III, negative estrogen and progesterone receptors, and high proliferative rate; group B (n = 20) was characterized by grade I-II tumors, positive hormonal receptors, and low proliferative rate; and group C (n = 58) was not homogeneous for the histopathological criteria. The aim of our study was to evaluate, in patients with a family history of breast cancer or with early diagnosis of breast cancer, the incidence of BRCA1 mutation on the basis of tumor phenotype. We found the highest rate of BRCA1 mutations in group A (53%), and low frequencies in groups B (5%) and C (0%). Our data strongly indicate that an aggressive tumor phenotype in patients with a positive family history or early diagnosis identifies a population with high probability of carrying BRCA1 mutations. Genes Chromosomes Cancer 27:130-135, 2000.     

Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile.     

Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences.

DNA replication errors (RERs) in repeated nucleotide sequences due to defective mismatch repair genes have been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC). We detected RER in 18 cases (13%) in a prospective series of 137 sporadic stage II and III (Dukes' B and C) colorectal carcinomas. The clinical and pathological features of the RER-positive cases differed from those without RER. The patients with RER-positive cancers tended to be somewhat younger (60 +/- 5 years, range 22-83, versus 66 +/- 1, range 27-90, P = 0.2 with unequal variances) and had a marked preponderance of tumors proximal to the splenic flexure (17/18, 94%, versus 41/119, 34%, P < 0.0001). Only two RER-positive patients (11%) had a family history of colorectal cancer. In comparison to the 41 RER-negative proximal colonic cancers, RER-positive cancers had more frequent exophytic growth (P = 0.04), large size (P = 0.03), poor differentiation (P = 0.0004), extracellular mucin production (P = 0.003) and Crohn's-like lymphoid reaction (P = 0.003), and a trend toward less frequent p53 gene product overexpression by immunohistochemistry (3/17, 18%, versus 18/41, 44%, P = 0.06). We conclude that a subset of sporadic colorectal carcinomas has unique biological features that may indicate inherited germline mutation, de novo germline mutation, or somatic mutations of the mismatch repair genes involved in HNPCC.     

Prediction of BRCA1/2 mutation status in patients with ovarian cancer from a hospital-based cohort.

PURPOSE: To describe patient, tumor, and family histories of cancer in a hospital-based cohort of patients with ovarian cancer and to identify the predictive value of these characteristics for (non)carrying a BRCA1 or BRCA2 mutation. METHODS: Women diagnosed with invasive ovarian cancer between 1999 and 2003 in the west region of The Netherlands and unselected for age at diagnosis or cancer family history were included. Information was gathered on patient and tumor characteristics; p53; HER-2/neu, and KI-67 protein-expression; BRCA1/2 mutations; and family histories of cancer. Prediction tests were constructed using multivariate analyses. RESULTS: Our study included 85 women (mean age at diagnosis, 57.6 years; standard deviation, 11.0 years). Six of these women had been previously or concurrently diagnosed with another tumor. Of the ovarian cancers, 41 (48.2%) were in an early stage (FIGO I or II). Five pathogenic mutations (6.1%) and six unclassified variants (7.3%) were identified in BRCA1/2; when the total sensitivity of the mutation scanning was taken into account, it was estimated to reflect seven pathogenic mutations (8.5%) and eight unclassified variants (9.8%). Sixty-nine women (81.2%) had at least one relative with cancer. A personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer were found to predict the presence of pathogenic mutations. CONCLUSION: As the combination of a personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer had good predictive value for the presence of a pathogenic BRCA1/2 mutation, the presented prediction test is a useful instrument to identify those women eligible for DNA testing.     

Cancer incidence in old age

The incidence of all cancer increases with age through most of the human life span, but its real incidence at very old ages has not been well elucidated to date. Clarification of the real incidence of cancer in old age, especially among centenarians, may well provide pivotal information to understand the characteristics of humankind. In this study, autopsy records of the Annual of the Pathological Autopsy Cases in Japan, 1991-1996, vols. 34-39 (Japanese Society of Pathology, Tokyo) were used. Cases over 90 years old were studied individually for accurate analysis. The incidence of cancer peaked in the 6th decade and that of multiple cases in the 8th decade. In groups over 90 years of age, the incidence at 5-year intervals did not show any significant decrement. Moreover, the metastatic rate and rate of death due to cancer among centenarians was about three-fourths and two-thirds, respectively, of that of cases aged 90-94 years. The decrease in the metastatic ratio and less mortality due to cancer occurring at the oldest ages are considered due to the nature of cancer itself. The fact that the incidence of cancer does not increase would suggest that certain people among those of advanced age have a special resistance to it.     

Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer

Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various tumors, including breast cancer. However, it still remains unclear whether the alterations in mtDNA are related to the clinicopathological features and/or the prognosis in the breast cancer. We analyzed somatic mutations in the D-loop region, the common 4,977-bp deletion, and the copy number of mtDNA in breast cancer and paired nontumorous breast tissues from 60 Taiwanese patients. We found that 18 of the 60 (30%) breast cancers displayed somatic mutations in mtDNA D-loop region. The incidence of the 4,977-bp deletion in nontumorous breast tissues (47%) was much higher than that in breast cancers (5%). The copy number of mtDNA was significantly decreased in 38 of the 60 (63%) breast cancers as compared to their corresponding nontumorous breast tissues (P = 0.0008). The occurrence of D-loop mutations was associated with an older onset age (>or=50 years old, P = 0.042), and tumors that lacked expressions of estrogen receptor and progesterone receptor (P = 0.024). Patients with mtDNA D-loop mutation and breast cancer had significantly poorer disease-free survival than those without mutation, when assessed by Kaplan-Meier curves and log-rank test (P = 0.005). Multivariate Cox regression analysis indicated that a D-loop mutation is a significant marker that is independent of other clinical variables and that it can be used to assess the prognosis of patients. Our findings suggest that somatic mutations in mtDNA D-loop can be used as a new molecular prognostic indicator in breast cancer.     

Defective mismatch-repair colorectal cancer: clinicopathologic characteristics and usefulness of immunohistochemical analysis for diagnosis

The purpose of our study was to determine the usefulness of immunohistochemical analysis for the diagnosis of mismatch-repair (MMR) gene defective colorectal tumors and to describe their prevalence and clinicopathologic characteristics. We studied 172 cases. DNA was extracted from formalin-fixed, paraffin-embedded surgical samples, and microsatellite analysis was performed by polymerase chain reaction with BAT-26. The results were correlated with immunohistochemical analysis for hMLH1 and hMSH2. Microsatellite instability (MSI) was detected in 13 (7.6%) tumors, and all showed loss of protein expression of hMLH1 (11/13) or hMSH2 (2/13) (P < .000). Patients with MMR-defective tumors more frequently had poorly differentiated tumors (5/13 [38%] vs 18/159 [11.3%]; P = .02) located in the ascending colon (8/13 [62%] vs 30/159 [18.9%]; P < .0001) and a personal history of other neoplasms (4/13 [31%] vs 18/159 [11.3%]; P = .05). There were no differences in age, family history of cancer, or TNM stage. Immunohistochemical analysis seems to be a reliable method to detect most colorectal cancers with defective MMR genes.     

Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France

The prevalence of BRCA1/2 germ-line mutations was assessed in a prospective population-based series of early-onset breast cancer (BC) patients in France, and the usefulness of a clinical assessment of hereditary BC risk, based on multiple criteria including pedigree structure, was evaluated. Through the Rhone region BC registry, 232 women diagnosed with BC before 46 years of age were included. They were tested for BRCA1/2 mutations an average of 10 months after diagnosis. All the women were classified according to their family history of cancer: high risk of hereditary breast cancer (HBC), low risk of HBC, isolated BC, and unknown HBC risk. Deleterious mutations were observed in 21 women (9.1%): 15 (6.5%) BRCA1 and 6 (2.6%) BRCA2. Mutations were more prevalent in women who developed BC before age 41 than in women who developed BC between ages 41 and 45 (12.8% versus 5.2%, respectively, P = 0.04). A high prevalence of BRCA1/2 mutations was found among women in the high-risk category with particular family features (i.e., small family size, predominantly male pedigree, specific cancers; 23.5%) and among women with isolated BC before age 41 and with five or fewer close adult female relatives (16.6%). According to the 10% probability level recommended by the American Society of Clinical Oncology guidelines for genetic testing of cancer, BRCA1/2 mutation screening should be considered for all women diagnosed before age 41, except for those with isolated BC in a large pedigree including multiple unaffected female relatives. The clinical assessment of HBC risk that we have developed should help in the decision to perform genetic testing.     

Nuclear DNA content as a prognostic factor in T1-2N0 breast cancer

One hundred fifteen patients with postsurgical stage T1-2N0 breast cancer with the minimum follow-up of 22 years and from a defined population were studied to find reliable prognostic factors predicting long-term survival rate. The 30-year survival rate corrected for intercurrent deaths was 75%, and no deaths of breast cancer occurred after the nineteenth year of follow-up. The 30-year crude survival rate was only 28%, indicating that the great majority of these patients ultimately die of other causes than breast cancer. The nuclear DNA content could be determined by flow cytometry in 95 of the 115 cases, and 52 (55%) of them were nondiploid. DNA ploidy (diploid vs. nondiploid, P = 0.11) did not have a significant influence on long-term survival rate, but cancers with the DNA index less than 1.2 had more favorable prognosis in a univariate analysis than those with the DNA index more than 1.2 (P = 0.02). The most important independent prognostic factor in Cox's multivariate analysis was the presence of lymphatic vessel invasion of cancer cells (P less than 0.001). Several other factors, including histologic grade and type, extent of necrosis, type of tumor margin, age at diagnosis, and primary tumor size could be shown to be of prognostic value in univariate and/or multivariate analyses.     

Human epidermal growth factor receptor 2, Na+/H+ exchanger regulatory factor 1, and breast cancer susceptibility gene-1 as new biomarkers for familial breast cancers

The aim of this study is to evaluate the analysis of markers related with progression, to further characterize familial breast cancers. Here, we investigated the expression of breast cancer susceptibility gene-1, hypoxia-inducible factor-1α, vascular endothelial growth factor receptor 1, and Na+/H+ exchanger regulatory factor 1 in 187 microarrayed breast carcinomas from 94 familial and 93 sporadic breast cancer patients by immunohistochemical staining. Furthermore, the expression levels of these biomarkers were compared with triple-negative phenotype. Familiarity was significantly associated with younger age (P < .000), higher tumor grade (P = .038), negative estrogen receptor hormonal status (P = .036), and high proliferative activity (P = .029). The familial cancers were immunonegative for membranous Na+/H+ exchanger regulatory factor 1 expression compared with sporadic cancers (P = .001); notably, vascular endothelial growth factor receptor 1 staining correlated with cytoplasmic Na+/H+ exchanger regulatory factor 1 expression in familial tumors (P = .009). In multivariate analysis, the "new biomarkers," including negative human epidermal growth factor receptor 2 status (odds ratio, 4.538; 95% confidence interval, 1.756-11.728), negative membranous Na+/H+ exchanger regulatory factor 1 expression (odds ratio, 7.686; 95% confidence interval, 1.876-31.483) and positive nuclear breast cancer susceptibility gene-1 (odds ratio, 0.3982; 95% confidence interval, 0.169-0.936), significantly correlated with family history of breast cancer. We hypothesize that the evaluation of human epidermal growth factor receptor 2, Na+/H+ exchanger regulatory factor 1, and breast cancer susceptibility gene-1 could be clinically useful to identify familial breast tumors and to select patients candidate to breast cancer susceptibility genes 1/2 gene sequencing.     

Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome

PurposeThis study aimed to characterize MSH6/PMS2-associated mismatch repair–deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes.MethodsPatients who consented to Institutional Review Board–approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests.ResultsWe identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years.ConclusionMSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.     

CpG island methylation in familial colorectal cancer patients not fulfilling the Amsterdam criteria

To determine the role of methylation in colorectal cancer patients with a family history, we enrolled 25 colorectal cancer patients with a family history of colorectal cancer but without a mutation in the hMLH1 and hMSH2 genes. Thirty patients with sporadic colorectal cancer were included as control. The methylation status of COX2, MGMT, hMLH1, TIMP3, p16, and MINT2 in normal mucosa and tumor were assessed using methylation-specific PCR. In patients with a family history, the methylation frequency ranged from 4.0% for TIMP3 to 44.4% for MGMT, whereas, in patients with sporadic colorectal cancer, it ranged from 6.7% for TIMP3 to 50.0% for p16. Nine of the 25 patients with family history (36.0%) were classified as methylation-prone, and nine of the 30 patients with sporadic cancers (30.0%) were as methylation-prone, making their methylation indices 0.19 and 0.16, respectively (p=0.522). As for the individual genes, the methylation rate of MGMT was higher in colorectal cancer patients with family history (44.0% vs. 13.0%, p=0.016), whereas the methylation rate of p16 was higher in sporadic colorectal cancers (50.0% vs. 8.7%, p=0.046). While CpG island methylation of tumor suppressor genes may play a role in colorectal carcinogenesis, the genes involved may be different between tumors of patients with and without a family history of colorectal cancer.     

Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis.

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome that is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability. In this study, we examined microsatellite instability and the clinicopathologic features of urothelial carcinoma of the renal pelvis (n = 61) and ureter (n = 53) from 114 consecutive patients surgically treated from 1985-1992. Clinical data were obtained through chart review. Matched normal and tumor DNA was extracted from paraffin-embedded tissue, and a panel of six microsatellite loci was analyzed. The male-female ratio was 2.8:1 with a median age of 70 years (range, 28 to 92 y). Microsatellite analysis was successful in 67 tumors, and 21 (31.3%) patients had tumors that exhibited microsatellite instability. Patients with microsatellite-unstable tumors were significantly more likely to have additional nonurologic cancers (P =.015) including colorectal carcinoma (P =.001) compared with patients with tumors that did not exhibit microsatellite instability. In addition, patients with microsatellite-unstable tumors showed more colorectal cancers in their family (P =.026) and were more likely to have higher grade urothelial carcinoma of the upper tract (P =.028). Grade and stage, but not microsatellite status, were the strongest predictors of cancer-specific survival. This study found the highest frequency of microsatellite instability in upper urothelial tract carcinomas reported to date and highlights upper tract urothelial carcinoma as a marker of the hereditary nonpolyposis colorectal cancer syndrome in some patients. These findings reinforce the importance of obtaining cancer histories in patients with upper tract urothelial carcinoma to subsequently identify individuals with the hereditary nonpolyposis colorectal cancer syndrome and at-risk relatives for surveillance and management programs.     

Head and neck cancer--a clinicopathological study in a tertiary care center

Head and neck cancers display diverse patterns of biological behavior and considerable variation in geographical distribution. This study presents an analysis of head and neck cancer in a Nigerian tertiary healthcare center. It comprises cases diagnosed at the University College Hospital, Ibadan, Nigeria, 1991-2005. Out of 1,750 head and neck tumors, 972 (55.5%) were malignant and 778 (44.5%) were benign. Cancers displayed male predominance, with a gender ratio of 1.8:1. The mean age of cancer patients was 43.8 +/- 19.6 years. Carcinomas constituted 71.7% of head and neck cancers, with 2.4% occurring in children and overall mean age of 48.2 years. Squamous cell carcinoma comprised 66.7% of carcinomas and 47.8% of all head and neck cancers. Hematopoietic malignancies constituted 20.4% of head and neck cancers, and comprised mainly lymphomas, which accounted for 19.3% of all head and neck cancers. The mean age of patients with hematopoietic malignancies was 34.9 years. The most common childhood malignancy was Burkitt's lymphoma, which comprised 28.2% of pediatric head and neck cancers. Connective tissue tumors constituted 7.9% of all cancers, the most common being rhabdomyosarcoma, accounting for 44.2% of sarcomas. The mean age of patients with sarcomas was 26.5 years. There is a need for uniformity in the definition of head and neck cancer so as to permit comparison of international studies. In addition, prospective population-based studies are required to determine the national incidence and to identify risk factors for head and neck cancer in the Nigerian population.