A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
CLL; NHL; SNPs; BAK1; risk locus
Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia (CLL) is constrained by intolerance of myelosuppression and the risk of exacerbation of autoimmune cytopenia by purine analogs particularly when used as single agents. We report on 20 such patients treated with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Autoimmune cytopenia responded in 19 patients (14 complete remissions (CR), five partial remissions (PR)) with a median time to next treatment (TTT) for autoimmune cytopenia of 21.7 months. Progressive CLL responded in 17 patients (nine CR/complete clinical response, eight PR) with a median TTT of 27.7 months. Five patients have not required any re-treatment at 15–30 months. Grade 3–4 toxicities were infections (n = 3) and drug-induced pneumonitis (n = 1). No patient required blood cell transfusions after cycle 1 of therapy. We conclude that R-CVP is effective and tolerable therapy for autoimmune cytopenia complicating progressive CLL, but the duration of response is suboptimal.
Chronic lymphocytic leukemia; autoimmune hemolytic anemia; immune thrombocytopenia; pure red blood cell aplasia; therapy
New-onset diabetes mellitus (DM) may herald pancreatic cancer (PaC). We determined if changes in body weight distinguished PaC-associated DM (PaCDM) from type 2 DM.
Amongst Olmsted County residents, we identified 29 PaCDM and 43 type 2 DM subjects who had serial fasting blood glucose (FBG) measurements, new-onset DM and no cancer-specific symptoms at DM onset. We compared body weight (kg) and FBG (mg/dl) at DM onset, 1–2 years prior and at index date in the two groups.
FBG values were similar prior to and at the onset of DM. Prior to onset of DM, PaCDM and type 2 DM had similar body weight (P=.80). However, at onset of DM 59% of PaCDM lost weight vs. 30% of type 2 DM (P =.02). At onset of DM, 56% of type 2 DM gained weight vs. 31% of PaCDM (P=.04). By index date, PaCDM lost more weight than type 2 DM (8.3±8.3 vs. 0.8±4.8 kg,P<.01).
While new-onset primary type 2 DM is typically associated with weight gain, weight loss frequently precedes onset of PaCDM. The paradoxical development of diabetes in the face of ongoing weight loss may be an important clue to understanding the pathogenesis of PaCDM.
Pancreatic cancer; New-onset diabetes mellitus; zinc alpha-2 glycoprotein
Pancreatic cancer (PC) is considered the most lethal cancer and approximately 10% of PC is hereditary. The purpose of the study was to assess attitudes of at-risk family members with two or more relatives affected with pancreas cancer (PC) toward PC risk and future screening options.
At-risk family members and primary care controls were surveyed regarding perceived PC risk, PC worry/concern, attitude toward cancer screening, screening test accuracy, and intentions regarding PC screening via blood testing or more invasive endoscopic ultrasound (EUS).
PC family members reported greater perceived risk of PC than controls (54% vs. 6%, respectively, p < 0.0001). PC family members also reported higher levels of PC worry/concern than controls (p < 0.0001), although 19% of PC family members indicated they were “not at all concerned” about getting PC. PC family members indicated greater acceptance of a false-negative result on a PC screening test relative to controls (12% vs. 8%, p = 0.02). Both groups reported high (>89%) receptivity to the potential PC screening options presented, though receptivity was greater among PC family members as compared to controls (p < 0.0001) for EUS. In multivariable analyses, degree of PC concern (p < 0.0001) was associated with intention to screen for PC by blood test and EUS, while perceived PC risk was associated with likelihood of undergoing EUS only (p < 0.0001).
Receptivity to screening options for PC appears high. Clinicians should address behavioral and genetic risk factors for PC and foster appropriate concern regarding PC risk among at-risk individuals.
Pancreatic cancer; Health behavior; Perceived risk; Screening intentions
Germline mutations in CDKN2A have been reported in pancreatic cancer families, but genetic counseling for pancreatic cancer risk has been limited by lack of information on CDKN2A mutation carriers outside of selected pancreatic or melanoma kindreds. Lymphocyte DNA from consecutive, unselected white non-Hispanic patients with pancreatic adenocarcinoma was used to sequence CDKN2A. Frequencies of mutations that alter the coding of p16INK4 or p14ARF were quantified overall and in subgroups. Penetrance and likelihood of carrying mutations by family history were estimated. Among 1537 cases, 9 (0.6%) carried germline mutations in CDKN2A, including three previously unreported mutations. CDKN2A mutation carriers were more likely to have a family history of pancreatic cancer (P=0.003) or melanoma (P=0.03), and a personal history of melanoma (P=0.01). Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer (95% confidence interval (CI) 8–86%), and 39% for melanoma (95% CI 0–80). Among cases who ever smoked cigarettes, the risk for pancreatic cancer was higher for carriers compared with non-carriers (HR 25.8, P=2.1 × 10−13), but among nonsmokers, this comparison did not reach statistical significance. Germline mutations in CDKN2A among unselected pancreatic cancer patients are uncommon, although notably penetrant, especially among smokers. Carriers of germline mutations of CDKN2A should be counseled to avoid tobacco use to decrease risk of pancreatic cancer in addition to taking measures to decrease melanoma risk.
cyclin-dependent kinase inhibitor p16; genes; p16; pancreatic neoplasms
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
Spiral computed tomography (SCT) is being evaluated as a screening tool for lung cancer. Our objective was to describe the effect of participation in SCT screening on participants’ risk perceptions, worry, and expectations regarding the accuracy of the screening result.
We surveyed sixty individuals with lung cancer family history who were participating in a SCT study for the primary purpose of improving genetic linkage analysis at baseline, and then 1 and 6 months post SCT.
Of the sixty participants, forty received normal results, nineteen received non-negative results requiring follow-up, and one was diagnosed with lung cancer. At baseline, participants reported high levels of perceived lung cancer risk (64%), were concerned about getting lung cancer (94%) and the majority (84%) were not OK with receiving a non-negative SCT result. At 1 month post SCT, those with a non-negative screen (n=19) had lowered their expectations of test accuracy regarding non-negative results (54%) and reported increased levels in worry/concern (100%) and perceived risk (75%), but these effects diminished over time and returned almost to baseline levels at 6 months.
Persons at very high empiric risk for lung cancer expect their SCT screening test to be accurate and present with high levels of lung cancer risk perception and worry/concern overall. Our findings suggest a need for risk counseling and discussion on the limitations of screening tests to accurately detect lung cancer.
spiral computed tomography; lung cancer; screening; psychosocial oncology
Approximately 10% of pancreatic ductal adenocarcinomas have a familial basis. While a small portion of this familial clustering can be explained by inherited mutations in known genes (BRCA2, p16/CDKN2A, PRSS1, and STK11), the genetic basis for the majority of this familial clustering remains unknown. In addition, a pancreatic cancer susceptibility locus has been reported to be linked to chromosome 4q32-34 in a single family having a high penetrance of early-onset pancreatic ductal adenocarcinoma and pancreatic insufficiency. The goal of this study is to determine if linkage to chromosome 4q exists in our series of well-characterized families with idiopathic familial pancreatic cancer enrolled in the Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE).
Parametric and nonparametric linkage analyses were performed using 21 microsatellite markers on chromosome 4 on affected individuals with pancreatic cancer from 42 familial pancreatic cancer kindreds.
Markov Chain Monte Carlo parametric and nonparametric linkage analyses using SIMWALK2 as well as nonparametric linkage analysis using MERLIN did not provide strong evidence of linkage in this region (LOD < 1.0). Only one family provided a multipoint LOD score of >0.5 adjacent to the reported region.
Our results do not support linkage to the 4q32-34 region in the majority of our familial pancreatic cancer kindreds. However, because multiple pancreatic cancer susceptibility genes are likely to exist, it is possible that a subset of the families in this study may be linked to this region.
pancreatic cancer; genetics; linkage analysis; adenocarcinoma; familial pancreatic cancer; hereditary; gastrointestinal cancer
Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for < 0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder; no DNA mismatch repair defect was evident, and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. The occurrence of appendiceal cancer in siblings may represent a random occurrence. An exceedingly rare predisposition syndrome cannot be ruled out.
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
IRF4; CLL; genetic association
Deletion 13q14 on fluorescence in situ hybridization (FISH) analysis is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and is a favorable prognostic biomarker when detected as a sole abnormality. We intensively interrogated clinical outcome in 323 consecutive, untreated CLL patients with isolated 13q- identified within two years of diagnosis. We also analyzed outcome in 217 additional patients with deletion 11q22.3 or 17p13.1, or trisomy 12 based on whether these occurred in isolation or in conjunction with 13q-. Patients with a heterozygous 13q- and those with a homozygous deletion had similar time to first treatment (TFT) and overall survival (OS). In contrast, a higher percentage of 13q- nuclei was associated with significantly shorter TFT (p<0.001). The 5-year untreated rate was 79% for patients with isolated 13q- in ≤65.5% of nuclei compared to 38% among those with 13q- in >65.5% of nuclei (p<0.001). The percentage of nuclei exhibiting 13q- remained an independent predictor of TFT after controlling for ZAP-70, IgVH, or CD38 (all p<0.001). Among patients with 13q- plus one other FISH abnormality, concomitant 13q- appeared to attenuate the shorter survival associated with 17p- (p=0.019). The clinical implications of 13q- in CLL appear more complex than originally appreciated.
Chronic lymphocytic leukemia; 13q deletion; 17p deletion
Genomic imprinting refers to a parent-of-origin specific effect on gene expression. At least 1% of genes in the human genome are modulated in this manner. We sought evidence for genomic imprinting in colorectal cancer by studying the ages at diagnosis in the offspring of 2,061 parent-child pairs in which both parent and child were affected by non syndromic colorectal cancer. Families were ascertained through the colon Cancer Family Registry [http://epi.grants.cancer.gov/CFR/] from both population-based and clinic-based sources. We found that the affected offspring of affected fathers were on average younger than offspring of affected mothers (55.8 vs 53.7 years; p=0.0003), but when divided into sons and daughters, this difference was driven entirely by younger age at diagnosis in daughters of affected fathers compared to sons (52.3 years vs 55.1 years; p=0.0004). A younger age at diagnosis in affected daughters of affected fathers was also observable in various subsets including families that met Amsterdam II Criteria, families that did not meet Amsterdam Criteria, and in families with documented normal DNA mismatch repair in tumors. Imprinting effects are not expected to be affected by the sex of the offspring. Possible explanations for these unexpected findings include: 1) an imprinted gene on the pseudoautosomal regions of the X chromosome; 2) an imprinted autosomal gene that affects a sex-specific pathway; or 3) an X-linked gene unmasked because of colonic tissue-specific preferential inactivation of the maternal X chromosome.
imprinting; gender; pseudoautosomal; X-linked
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are common in white persons and are associated with pancreatic disease. The purpose of this case-control study was to determine whether CFTR mutations confer a higher risk of pancreatic cancer.
In a case-control study, we compared the rates of 39 common cystic fibrosis–associated CFTR mutations between 949 white patients with pancreatic adenocarcinoma and 13,340 white controls from a clinical laboratory database for prenatal testing for CFTR mutations. The main outcome measure was the CFTR mutation frequency in patients and controls.
Overall, 50 (5.3%) of 949 patients with pancreatic cancer carried a common CFTR mutation versus 510 (3.8%) of 13,340 controls (odds ratio, 1.40; 95% confidence interval, 1.04–1.89; P=.027). Among patients who were younger when their disease was diagnosed (<60 years), the carrier frequency was higher than in controls (odds ratio, 1.82; 95% CI, 1.14–2.94; P=.011). In patient-only analyses, the presence of a mutation was associated with younger age (median 62 vs 67 years; P=.034). In subgroups, the difference was seen only among ever-smokers, (60 vs 65 years, p=.028). Subsequent sequencing analysis of the CFTR gene detected 8 (16%) compound heterozygotes among the 50 patients initially detected to have 1 mutation.
Carrying a disease-associated mutation in CFTR is associated with a modest increase in risk for pancreatic cancer. Those affected appear to be diagnosed at a younger age, especially among smokers. Clinical evidence of antecedent pancreatitis was uncommon among both carriers and noncarriers of CFTR mutations.
Pancreatic neoplasms; molecular epidemiology; cystic fibrosis transmembrane conductance regulator
The pathology and clinical course of patients with CD5+ chronic B-cell lymphoproliferative disorders, excluding those that present with typical chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) or mantle cell lymphoma, (i.e. CD5+B-CLPD) are poorly defined.
We studied patients with CD5+B-CLPD to 1) more completely define the clinical features and pathology of CD5+B-CLPD, 2) compare these features to patients presenting with typical CLL, and 3) test the hypothesis that a subset of patients with CD5+B-CLPD could have a unique B-cell malignancy.
We identified 229 patients with CD5+B-CLPD. A definitive pathological diagnosis was made in all 61 (27%) CD5+B-CLPD patients with non-bone marrow (BM) biopsy specimens considered adequate for a comprehensive pathological examination. The most common diagnosis among these 61 patients was CLL (44%) followed by the leukemic phase of marginal zone lymphoma (34%), lymphoplasmacytic lymphoma (11%), diffuse large B cell lymphoma (8%), and high grade B cell lymphoma not otherwise specified (2%). In contrast, among 168 patients without a non-BM tissue biopsy specimen, a specific diagnosis could be made on review of all available data in only 24 (14%) with 144 (86%) remaining “unclassified”.
In patients with CD5+B-CLPD, a definitive diagnosis can be made on an adequate non-BM tissue biopsy suggesting that this entity does not include a novel disease. We recommend that all patients with CD5+B-CLPD should have a non-BM tissue biopsy to make a definitive diagnosis prior to initiation of treatment.
CD5; chronic lymphoproliferative disorders; CLL; SLL; lymphoma
The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients with a circulating population of clonal B cells, a total B-cell count of less than 5 × 109/L, and no other features of a B-cell lymphoproliferative disorder including lymphadenopathy/organomegaly. The natural history of clinically identified MBL is unclear. The goal of this study was to explore the outcome of patients with MBL relative to that of individuals with Rai stage 0 chronic lymphocytic leukemia (CLL).
Patients and Methods
We used hematopathology records to identify a cohort of 631 patients with newly diagnosed MBL or Rai stage 0 CLL. Within this cohort, 302 patients had MBL (B-cell counts of 0.02 to 4.99 × 109/L); 94 patients had Rai stage 0 CLL with an absolute lymphocyte count (ALC) ≤ 10 × 109/L; and 219 patients had Rai stage 0 CLL with an ALC more than 10 × 109/L. Data on clinical outcome were abstracted from medical records.
The percentage of MBL patients free of treatment at 1, 2, and 5 years was 99%, 98%, and 93%, respectively. B-cell count as a continuous variable (hazard ratio [HR] = 2.9, P = .04) and CD38 status (HR = 10.8, P = .006) predicted time to treatment (TTT) among MBL patients. The likelihood of treatment for MBL patients was lower (HR = 0.32, P = .04) than that of both Rai stage 0 CLL patients with an ALC less than 10 × 109/L (n = 94) and Rai stage 0 CLL patients with an ALC more than 10 × 109/L (n = 219; P = .0003).
Individuals with MBL identified in clinical practice have a low risk for progression at 5 years. Because B-cell count seems to relate to TTT as a continuous variable, additional studies are needed to determine what B-cell count should be used to distinguish between MBL and CLL.
Though the association between diabetes mellitus (DM) and pancreatic cancer is well described, temporal patterns of changes in fasting blood glucose (FBG) and body mass index (BMI) before pancreatic cancer diagnosis are not known.
We reviewed medical records of pancreatic cancer cases seen at Mayo Clinic from 1/15/1981 through 7/9/2004 and selected those residing within 120 miles of Rochester, Minnesota and seen at Mayo Clinic within 30 days from the date of cancer diagnosis (index date). We identified ~2 matched controls per case residing locally and seen at Mayo in the year of their case’s index date. For the 736 cases and 1,875 controls with at least one outpatient FBG measurement, we abstracted all FBG values and corresponding heights and weights up to 60 months before index and grouped them into 12-month intervals preceding index. We compared FBG and BMI in each interval between cases and controls.
Mean FBG values were similar between cases, compared to controls, in the −60 to −48 (102 vs. 100 mg/dl, p=0.34), and −48 to −36 month intervals (106 vs. 102 mg/dl, p=0.09); but progressively increased in the −36 to −24 (105 vs. 100 mg/dl, p=0.01), −24 to −12 (114 vs. 102 mg/dl, p=0.001), and −12 to +1 (123 vs. 102 mg/dl, p<.0001) month intervals. Though mean BMI values were generally similar in cases and controls up to 12 months before index, they were significantly lower in cases vs controls in the −12 to +1 (p<.001) month intervals.
Pancreatic cancer is characterized by progressive hyperglycemia beginning up to 24 months before cancer diagnosis in the setting of decreasing BMI. Pancreatic cancer can potentially be diagnosed early if biomarkers are identified that can distinguish pancreatic cancer-induced DM from type 2 DM.
Pancreatic cancer; diabetes; screening
Due to the growing need to combine data across multiple studies and to impute untyped markers based on a reference sample, several analytical tools for imputation and analysis of missing genotypes have been developed. Current imputation methods rely on single imputation, which ignores the variation in estimation due to imputation. An alternative to single imputation is multiple imputation. In this paper, we assess the variation in imputation by completing both single and multiple imputations of genotypic data using MACH, a commonly used hidden Markov model imputation method. Using data from the North American Rheumatoid Arthritis Consortium genome-wide study, the use of single and multiple imputation was assessed in four regions of chromosome 1 with varying levels of linkage disequilibrium and association signals. Two scenarios for missing genotypic data were assessed: imputation of untyped markers and combination of genotypic data from two studies. This limited study involving four regions indicates that, contrary to expectations, multiple imputations may not be necessary.
Several methods have been proposed to impute genotypes at untyped markers using observed genotypes and genetic data from a reference panel. We used the Genetic Analysis Workshop 16 rheumatoid arthritis case-control dataset to compare the performance of four of these imputation methods: IMPUTE, MACH, PLINK, and fastPHASE. We compared the methods' imputation error rates and performance of association tests using the imputed data, in the context of imputing completely untyped markers as well as imputing missing genotypes to combine two datasets genotyped at different sets of markers. As expected, all methods performed better for single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium with genotyped SNPs. However, MACH and IMPUTE generated lower imputation error rates than fastPHASE and PLINK. Association tests based on allele "dosage" from MACH and tests based on the posterior probabilities from IMPUTE provided results closest to those based on complete data. However, in both situations, none of the imputation-based tests provide the same level of evidence of association as the complete data at SNPs strongly associated with disease.
The temporal association between diabetes mellitus and pancreatic cancer is poorly understood. We compared temporal patterns in diabetes prevalence in pancreatic cancer and controls.
We reviewed medical records of pancreatic cancer cases residing ≤120 miles of Rochester seen at Mayo Clinic between 1/15/1981 and 7/9/2004 and approximately two matched controls/case residing locally. We abstracted all outpatient fasting blood glucose (FBG) up to 60 months before index i.e., date of cancer diagnosis for cases and grouped them into 12-month intervals; 736 cases and 1875 controls had ≥1 outpatient FBG in the medical record. Diabetes was defined as any FBG ≥126 mg/dl or treatment for diabetes and as new-onset when criteria for diabetes were first met ≤24 months before index, with at least one prior FBG <126 mg/dl.
A higher proportion of pancreatic cancer cases compared to controls met criteria for diabetes at any time in the 60 months before index (40.2% vs 19.2%, p<0.0001). The proportions were similar in the −60 to −48 (p=0.76) and −48 to −36 (p=0.06) month time periods; however, a greater proportion of cases than controls met criteria for diabetes in the −36 to −24 (p=0.04), −24 to −12 (p<0.001) and −12 to 0 (p<0.001) month time periods. Diabetes was more often new-onset in cases versus controls (52.3% vs 23.6%, p<0.0001).
Diabetes has a high (40%) prevalence in pancreatic cancer and is frequently new-onset. Identification of a specific biomarker for pancreatic cancer-induced diabetes may allow screening for pancreatic cancer in new-onset diabetes.
Background and Aims
In the last fifteen years, several single-gene Mendelian disorders have been discovered that may account for some of the familial aggregation detected in large population studies of colorectal cancer (CRC). Mutations in DNA mismatch repair (MMR) genes cause HNPCC-Lynch Syndrome, the most common of the recognized CRC-predisposition syndromes, in which one major feature is a young age for cancer onset. However, for young onset microsatellite stable( MSS) CRC, the familial risk for CRC is unknown.
Cases with CRC < 50 years old were identified through Minnesota Cancer Surveillance System (MCSS), and Mayo Clinic, Rochester, MN. CRC in which the DNA MMR function was deficient as evidenced by high level microsatellite instability and/or loss of expression of MMR gene product by immunostaining were excluded. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included. Data on 1862 relatives were collected, of whom 68 were found to have had CRC and an additional 165 had primary cancers of other types.
Compared to SEER data, relatives of young onset CRC probands had increased risks for CRC. This relative risk was increased among first degree relatives (RR=1.65; 95% C.I.=1.29–2.07), and was greater for siblings (RR = 2.67; 95% C.I=1.50–4.41) than parents (RR= 1.5; 95% C.I.=1.14–1.94)
We studied 278 probands with young-onset microsatellite stable CRC. We determined that the relative risk for CRC was greatest in siblings, which is consistent with an autosomal recessive inheritance pattern.
Background & Aims
Although diabetes occurs frequently in pancreatic cancer, the value of new-onset diabetes as a marker of underlying pancreatic cancer is unknown.
We assembled a population-based cohort of 2122 Rochester, Minnesota, residents age ≥50 years who first met standardized criteria for diabetes between January 1, 1950, and December 31, 1994, and identified those who developed pancreatic cancer within 3 years of meeting criteria for diabetes. We compared observed rates of pancreatic cancer with expected rates based on the Iowa Surveillance Epidemiology and End Results registry. In a nested case control study, we compared body mass index (BMI) and smoking status in diabetes subjects with and without pancreatic cancer.
Of 2122 diabetic subjects, 18 (0.85%) were diagnosed with pancreatic cancer within 3 years of meeting criteria for diabetes; 10 of 18 (56%) were diagnosed <6 months after first meeting criteria for diabetes, and 3 were resected. The observed-to-expected ratio of pancreatic cancer in the cohort was 7.94 (95% CI, 4.70–12.55). Compared with subjects without pancreatic cancer, diabetic subjects with pancreatic cancer were more likely to have met diabetes criteria after age 69 (OR = 4.52, 95% CI, 1.61–12.74) years but did not differ significantly with respect to BMI values (29.2 ± 6.8 vs 26.5 ± 5.0, respectively). A larger proportion of those who developed pancreatic cancer were ever smokers (92% vs 69%, respectively), but this did not reach statistical significance.
Approximately 1% of diabetes subjects aged ≥50 years will be diagnosed with pancreatic cancer within 3 years of first meeting criteria for diabetes. The usefulness of new-onset diabetes as marker of early pancreatic cancer needs further evaluation.
The goal of this paper is to investigate the effect of using principal components as a data reduction method for expression data in linkage analysis. We used 45 probes normalized using the Affymetrix Global Scaling that had evidence of high heritability to estimate the first 10 principal components (PC). A genome-wide linkage scan was performed on the 45 expression values and the 10 PCs using 2272 single-nucleotide polymorphisms. Our conclusions were: 1) PC analyses under-performed the single-probe analysis for known signals; 2) the PC that best reproduced the single-probe analysis was primarily composed of that probe; 3) no new signals were detected in the PC analysis; 4) no new pleiotropic effects were detected in the PC analysis.
The goal of this paper is to investigate the effects of normalization procedures for expression data on linkage results. We selected the two most commonly used expression data extraction and normalization methods, Affymetrix global scaling and dChip invariant. After applying these two methods in 3554 expression phenotypes, we identified 45 phenotypes that were more likely to be genetic for either normalization procedure. A genome-wide linkage scan was performed on these expression values (45 phenotypes × 2 normalizations) using 2272 SNPs. Our results showed that: 1) the dChip normalization might inflate the LOD scores because the dChip normalization yielded LOD scores > 3.0 30% more frequently than the Affy normalization, and 2) the difference in LODs between the normalizations were not correlated with their heritabilities. In summary, we conclude, as have other published reports, that normalization methods play an important role in the linkage results, and that some significant linkage signals might be due to a specific normalization method.
Background & Aims
Pancreatic adenocarcinoma has been associated with several familial cancer syndromes that also predispose to other malignancies. Younger ages of onset of pancreatic cancer (PC) have been reported in families with these syndromes.
Six hundred twenty-four consecutive patients (probands) from the Mayo Clinic Pancreatic Cancer Patient Registry who completed questionnaires were analyzed for family history of cancer and cigarette smoking. The ages at diagnosis of those probands who reported a family history (first- or second-degree relative) of PC, breast, ovarian, colorectal cancer, or melanoma were compared with those probands who did not. Multivariable regression analyses were performed with age at diagnosis as the primary outcome variable.
As expected, smokers had a younger median age of onset of PC than nonsmokers in dose-dependent fashion (P = .0003). After controlling for tobacco exposure and gender, those probands with a family history of breast (−3.23 years, P = .001), ovarian (− 5.63 years, P = .005), colorectal (− 3.19 years, P = .002) cancers, and melanoma (− 5.75 years, P = .017) had a younger age of onset of PC than those who did not. Those with a family history of PC (−.61 years, P = .65) exhibited no difference. Probands reporting other cancers in relatives showed no difference (+.78 years, P = .49) in age of onset of PC.
A family history of cancers (breast, ovarian, colorectal, melanoma) associated with specific cancer syndromes that are known to contribute also to PC risk is associated with a younger onset of PC. A family history of PC does not appear to affect age of onset of PC.
We compared the results of quantitative linkage analysis using single-nucleotide polymorphisms and microsatellite markers and introduced a new screening test for multivariate quantitative linkage analysis using the Collaborative Study on the Genetics of Alcoholism data. We analyzed 115 extended non-Hispanic White families and tested for linkage using two phenotypes: the maximum number of drinks in a 24-hour period and the number of packs smoked per day for one year. Our results showed that the linkage signal increased using single-nucleotide polymorphisms compared with microsatellite markers and that the screening test gave similar results to that of the bivariate analysis, suggesting its potential use in reducing overall analysis time.