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Background & Aims: The colorectal adenoma is the precursor lesion in virtually all colorectal cancers. Occurrence of colorectal adenomas has been studied in older adults but analysis in younger adults is lacking. Methods: The prevalence by age, sex, race, and location, and the number of colorectal adenomas detected was investigated using epidemiologic necropsy in 3558 persons ages 20 to 89 autopsied from 1985 to 2004 at the Johns Hopkins Hospital. Results were standardized to the general population. Younger adults 20 to 49 years old were compared with older adults 50 to 89 years old. Results: The prevalence of colorectal adenomas in younger adults increased from 1.72% to 3.59% from the third to the fifth decade of life and then sharply increased after age 50. In younger adults, adenomas were more prevalent in men than in women (risk ratio, 1.09; 95% confidence interval, 1.07–1.11) and in whites than in blacks (risk ratio, 1.28; 95% confidence interval, 1.26–1.31). Overall, both younger and older adults had predominately left-sided adenomas, but blacks in both age groups had more right-sided adenomas. Occurrence of 2 or more adenomas in younger adults and 5 or more in older adults was greater than 2 SDs from the mean. Conclusions: Colorectal adenomas infrequently occur in younger adults and are more prevalent in the left colon. Irrespective of age, blacks have more right-sided adenomas, suggesting the need for screening the entire colorectum. Two or more adenomas in younger adults and 5 or more in older adults represents polyp burden outside the normal expectation.

Purpose To assess patient views regarding the value of genetic counselling for familial pancreas cancer in the absence of predictive genetic testing. Patients and methods At-risk adults with three or more relatives with pancreas cancer received genetic counselling prior to research screening via endoscopic ultrasound. Questionnaires were mailed after the visit to assess perceived value of the counselling session. Results Ninety-three percent of respondents felt genetic counselling for pancreas cancer was helpful despite the lack of a causative gene, while only 7% felt that it should not be offered until such a gene is discovered. Over half of respondents believed the pancreas cancer in their family was caused by a gene mutation, and 42% thought they had inherited the mutation. The average perceived lifetime risk of developing pancreas cancer was 51%, and 87% of respondents would ultimately seek predictive genetic testing. When more information is gained, 89% would be interested in another genetic counselling session, and 82% would recommend current genetic counselling for pancreas cancer to a friend or relative with a family history of the disease. Conclusion Despite the lack of an identified major causative gene for pancreas cancer, respondents found genetic counselling for this malignancy to be helpful. These patients perceive their personal cancer risk to be high, and would seek predictive genetic testing if it were available. Referral for genetic counselling should be offered to appropriate individuals.

Early and late effects of cancer treatment are of increasing concern with growing survivor populations, but relevant data are sparse. We sought to determine the prevalence and hazard ratio of such effects in breast cancer cases. Women with invasive breast cancer and women with no cancer history recruited for a cancer research cohort completed a mailed questionnaire at a median of 10 years post-diagnosis or matched reference year (for the women without cancer). Reported medical conditions including lymphedema, osteopenia, osteoporosis, and heart disease (congestive heart failure, myocardial infarction, coronary heart disease) were assessed in relation to breast cancer therapy and time since diagnosis using Cox regression. The proportion of women currently receiving treatment for these conditions was calculated. Study participants included 2,535 women with breast cancer and 2,428 women without cancer (response rates 66.0 % and 50.4 %, respectively) Women with breast cancer had an increased risk of lymphedema (Hazard ratio (HR) 8.6; 95 % confidence interval (CI) 6.3–11.6), osteopenia (HR 2.1; 95 % CI 1.8–2.4), and osteoporosis (HR 1.5; 95 % CI 1.2–1.9) but not heart disease, compared to women without cancer Hazard ratios varied by treatment and time since diagnosis. Overall, 49.3 % of breast cancer cases reported at least one medical condition, and at 10 or more years post-diagnosis, 37.7 % were currently receiving condition-related treatment. Responses from survivors a decade following cancer diagnosis demonstrate substantial treatment-related morbidity, and emphasize the need for continued medical surveillance and follow-up care into the second decade post-diagnosis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. Supported by NIH grants CA106610, CA62924 and CA140599, The George Rubis Endowment for Pancreatic Cancer Research, The Michael Rolfe Pancreatic Cancer Foundation, Sigma Beta Sorority, The Joseph C. Monastra Foundation, The Alfredo Scatena Memorial, The Patty Boshell Pancreas Cancer Foundation, and Grants SAF2007-60860 and ONCOBIO Consolder from Ministerio de Ciencia e Innovación, Madrid, Spain (F.R.). The authors have no financial conflicts of interest related to this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Background & Aims Patients with Lynch syndrome have a high risk for colorectal adenomas and carcinomas. We evaluated the development of colorectal neoplasia in these patients. Methods We assessed serial colonoscopy findings from 54 persons from 29 pedigrees with pathogenic mutations in MSH2 or MLH1; we evaluated the development of colorectal neoplasia by age, sex, tumor location, and number (mean follow-up time, 9.3 years; colonoscopy interval, 1.7 ± 1.2 years; 112 adenomas and 31 cancers). Differences in colorectal phenotype were analyzed by genotype, and dwell time was calculated for advanced neoplasias. Results Among mutation carriers, the cumulative risk of colorectal neoplasia was 43% by age 40 years and 72% by 80 years. There were no statistically significant associations between time to development of colorectal neoplasia and sex or mutation type. Most female patients had left-sided neoplasms, whereas most male patients developed right-sided lesions. The mean cumulative numbers of neoplastic lesions in patients were 1.3 ± 0.5 by age 30 years and 7.6 ± 6.8 by age 80 years. Polyp dwell time was 33.0 ± 16.2 months and 35.2 ± 22.3 months for advanced adenoma and colorectal cancer, respectively. The 5-year survival rate for patients with colorectal cancer was 96%. Conclusions High percentages of individuals with pathogenic mutations in MSH2 or MLH1 develop colorectal neoplasia by age 40. Left-sided colorectal neoplasias are more frequent in female patients. The development of 3 or more colorectal neoplasms by age 30 years indicates a possible polyposis syndrome rather than Lynch syndrome. Polyp dwell time is short for advanced neoplasias, arguing for annual colonoscopic screening and surveillance.

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

Objective: An exploratory analysis of co-aggregation of cancers using registry-based data. Methods: We utilized sibships from over 18,000 families who had been recruited to the NCI-sponsored multi-institutional Cancer Genetics Network. The analysis assesses co-aggregation at the individual and family level and adjusts for ascertainment. Results: We found statistically significant familial co-aggregation of lung cancer with pancreatic (adjusted p < 0.001), prostate (adjusted p < 0.003), and colorectal cancers (adjusted p = 0.004). In addition, we found significant familial co-aggregation of pancreatic and colorectal cancers (adjusted p = 0.018), and co-aggregation of hematopoietic and (non-ovarian) gynecologic cancers (adjusted p = 0.01). Conclusion: This analysis identified familial aggregation of cancers for which a genetic component has yet to be established.

Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5–16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22–6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2–74.7), two (6.4; CI, 1.8–16.4), or one (4.6; CI, 0.5–16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer.

Arsenic is effective in the treatment of acute promyelocytic leukemia. Paradoxically, it is also carcinogenic. In the process of elucidating a mechanism of arsenic resistance in a leukemia cell line, NB4, we discovered that arsenic exposure causes chromosomal abnormalities, with a preponderance of end-to-end fusions. These chromosomal end fusions suggested that telomerase activity may be inhibited by arsenic. We found that arsenic inhibits transcription of the hTERT gene, which encodes the reverse transcriptase subunit of human telomerase. This effect may in part be explained by decreased c-Myc and Sp1 transcription factor activities. Decreased telomerase activity leads to chromosomal end lesions, which promote either genomic instability and carcinogenesis or cancer cell death. These phenomena may explain the seemingly paradoxical carcinogenic and antitumor effects of arsenic.

Allogeneic bone marrow transplant engraftment assays use polymorphisms in the human genome to determine the relative percentages of donor and recipient cells present in the recipient. We describe a novel posttransplant assay approach using single nucleotide polymorphisms (SNPs), the most common type of polymorphism in humans. Using samples of defined genotype, we used real-time polymerase chain reaction (PCR) and allele-specific fluorescent TaqMan probes to assay a SNP of the cytochrome P450 CYP2C9 gene. Standard curves of chimeric mixes showed a linear relationship between the ratio of two alleles and the ratio of their respective fluorophore emission, except for mixes with a low percentage (

Therapy-related myeloid neoplasms (t-MN) are well-recognized complications of high-dose cytotoxic therapy (HDT), such as autologous stem cell transplantation (ASCT). Clonal marrow cytogenetic abnormalities (CMCA) in the setting of normal bone marrow pathology have also been reported after HDT, but their significance remains unclear. We retrospectively evaluated occurrences of CMCA and t-MN in 785 patients treated with HDT at Johns Hopkins University between 1997 and 2007. Most patients received ASCT, but 106 patients who received high-dose cyclophosphamide without ASCT were also included in this study, as this is our institutional standard for malignant and nonmalignant lymphoproliferative disorders in need of HDT. Twenty-two patients developed t-MN, with an estimated cumulative incidence of 3.5% at 4 years. Eleven patients developed isolated CMCA, either transient or persistent without pathologic evidence of t-MN. Altogether, only 20 of the patients with reported CMCA subsequently developed t-MN during the follow-up period. Therefore, in the absence of pathologic evidence of t-MN, CMCA should not be considered diagnostic of t-MN.

To date, 16 in utero hematopoietic stem cell (HSC) transplants for diseases other than immunodeficiency disorders have been reported. No therapeutic level of engraftment was detected in 15 of these transplants. To overcome engraftment failure, we transplanted a very large number (5 billion paternal CD34+ cells/kg) of HSCs to a fetus with leukodystrophy during the first trimester of gestation. As reported previously, the fetus died in utero 7 weeks after the procedure and the cause of death appeared to be overwhelming donor engraftment. In the present investigation, we developed a human-murine chimera model to test for the optimal donor cell dose for human in utero transplantation. We found a strong correlation between the level of donor engraftment in three human fetuses transplanted for leukodystrophy during the first trimester of gestation and the results of parallel xenotransplants of the same human donor cells using the NOD/SCID mouse model. This small animal model appears to predict both extremes of hyperengraftment (seen in the first human fetus transplanted) and engraftment failure (seen in the second and third human fetuses transplanted in utero). These and future correlated clinical and laboratory assay results may be useful for the development of in utero transplants for a variety of congenital disorders. Biol Blood Marrow Transplant 1999;5(1):1-7.

We have used three different methods to map the human liver/bone/kidney alkaline phosphatase (ALPL) locus: (1) Southern blot analysis of DNA derived from a panel of human-rodent somatic cell hybrids; (2) in situ hybridization to human chromosomes; and (3) genetic linkage analysis. Our results indicate that the ALPL locus maps to human chromosome bands 1p36.1-p34 and is genetically linked to the Rh (maximum lod score of 15.66 at a recombination value of 0.10) and fucosidase A (maximum lod score of 8.24 at a recombination value of 0.02) loci. These results, combined with restriction fragment length polymorphisms identified by ALPL DNA probes, provide a useful marker for gene mapping studies involving the short arm of chromosome 1. In addition, our results help to elucidate further the structure and evolution of the human alkaline phosphatase multigene enzyme family. © 1988.