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Aung Ko Win,
John L Hopper,
Daniel D Buchanan,
Joanne P Young,
Albert Tenesa,
James G Dowty,
Graham G Giles,
Jack Goldblatt,
Ingrid Winship,
Alex Boussioutas,
Graeme P Young,
Susan Parry,
John A Baron,
David Duggan,
Steven Gallinger,
Polly A Newcomb, Robert W Haile,
Loïc Le Marchand,
Noralane M Lindor,
Mark A Jenkins
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ABSTRACT: BACKGROUND: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. METHODS: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). RESULTS: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52). CONCLUSIONS: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.
European journal of cancer (Oxford, England: 1990) 02/2013; · 4.12 Impact Factor
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ABSTRACT: SCOPE: The metabolism of folate involves a complex network of polymorphic enzymes that may explain a proportion of the risk associated with colorectal neoplasia. Over 60 observational studies primarily in non-Hispanic White populations have been conducted on selected genetic variants in specific genes, MTHFR, MTR, MTRR, CBS, TCNII, RFC, GCPII, SHMT, TYMS, and MTHFD1, including five meta-analyses on MTHFR 677C>T (rs1801133) and MTHFR 1298C>T (rs1801131); two meta-analyses on MTR-2756A>C (rs1805087); and one for MTRR 66A>G (rs1801394). METHODS AND RESULTS: This systematic review synthesizes these data, highlighting the consistent inverse association between MTHFR 677TT genotype and risk of colorectal cancer (CRC) and its null association with adenoma risk. Results for other variants varied across individual studies; in our meta-analyses we observed some evidence for SHMT 1420C>T (rs1979277) ((odds ratio) OR = 0.85; 95% confidence interval (CI) = 0.73-1.00 for TT v. CC) and TYMS 5' 28 bp repeat (rs34743033) and CRC risk (OR = 0.84; 95% CI = 0.75-0.94 for 2R/3R v. 3R/3R and OR = 0.82; 95% CI = 0.69-0.98 for 2R/2R v. 3R/3R). CONCLUSION: To gain further insight into the role of folate variants in colorectal neoplasia will require incorporating measures of the metabolites, including B-vitamin cofactors, homocysteine and S-adenosylmethionine, and innovative statistical methods to better approximate the folate one-carbon metabolism pathway.
Molecular Nutrition & Food Research 02/2013; · 4.30 Impact Factor
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Aung Ko Win,
Noralane M Lindor,
Ingrid Winship,
Katherine M Tucker,
Daniel D Buchanan,
Joanne P Young,
Christophe Rosty,
Barbara Leggett,
Graham G Giles,
Jack Goldblatt, [......],
Susan Parry,
Matthew F Kalady,
John A Baron,
Dennis J Ahnen,
Loic Le Marchand,
Steven Gallinger, Robert W Haile,
Polly A Newcomb,
John L Hopper,
Mark A Jenkins
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ABSTRACT: Background
Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations.Methods
We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population.ResultsFollowing endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14).Conclusions
Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.
CancerSpectrum Knowledge Environment 02/2013; · 14.07 Impact Factor
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Aung Ko Win,
Susan Parry,
Bryan Parry,
Matthew F Kalady,
Finlay A Macrae,
Dennis J Ahnen,
Graeme P Young,
Lara Lipton,
Ingrid Winship,
Alex Boussioutas,
Joanne P Young,
Daniel D Buchanan,
Julie Arnold,
Loïc Le Marchand,
Polly A Newcomb, Robert W Haile,
Noralane M Lindor,
Steven Gallinger,
John L Hopper,
Mark A Jenkins
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ABSTRACT: BACKGROUND: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer. METHODS: This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method. RESULTS: During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III. CONCLUSIONS: Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.
Annals of Surgical Oncology 01/2013; · 4.17 Impact Factor
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Lenora W M Loo,
Maarit Tiirikainen,
Iona Cheng,
Annette Lum-Jones,
Ann Seifried,
James M Church,
Robert Gryfe,
Daniel J Weisenberger,
Noralane M Lindor,
Steven Gallinger, Robert W Haile,
David J Duggan,
Stephen N Thibodeau,
Graham Casey,
Loïc Le Marchand
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ABSTRACT: Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q. Within these genomic regions we identified 356 genes with significant differential expression (P < 0.0001 and ±1.5-fold change) in the tumor compared to adjacent normal tissue. Gene ontology and pathway analyses indicated that many of these genes were involved in functional mechanisms that regulate cell cycle, cell death, and metabolism. An amplicon present in >70% of the tumor samples at 20q11-20q13 contained several cancer-related genes (AHCY, POFUT1, RPN2, TH1L, and PRPF6) that were upregulated and demonstrated a significant linear correlation (P < 0.05) for gene dosage and gene expression. Copy number loss at 8p, a CNA associated with adenocarcinoma and poor prognosis, was observed in >50% of the tumor samples and demonstrated a significant linear correlation for gene dosage and gene expression for two potential tumor suppressor genes, MTUS1 (8p22) and PPP2CB (8p12). The results from our integration analysis illustrate the complex relationship between genomic alterations and gene expression in colon cancer. © 2013 Wiley Periodicals, Inc.
Genes Chromosomes and Cancer 01/2013; · 3.31 Impact Factor
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Mine S Cicek,
Julie M Cunningham,
Brooke L Fridley,
Daniel J Serie,
William R Bamlet,
Brenda Diergaarde, Robert W Haile,
Loic Le Marchand,
Theodore G Krontiris,
H Banfield Younghusband, [......],
Susan Parry,
Graeme P Young,
Joanne P Young,
Daniel Buchanan,
Duncan C Thomas,
D Timothy Bishop,
Noralane M Lindor,
Stephen N Thibodeau,
John D Potter,
Ellen L Goode
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Mine S Cicek,
Julie M Cunningham,
Brooke L Fridley,
Daniel J Serie,
William R Bamlet,
Brenda Diergaarde, Robert W Haile,
Loic Le Marchand,
Theodore G Krontiris,
H Banfield Younghusband, [......],
Susan Parry,
Graeme P Young,
Joanne P Young,
Daniel Buchanan,
Duncan C Thomas,
D Timothy Bishop,
Noralane M Lindor,
Stephen N Thibodeau,
John D Potter,
Ellen L Goode
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Xuejuan Jiang,
J Esteban Castelao,
David Vandenberg,
Angel Carracedo,
Carmen M Redondo,
David V Conti,
Jesus P Paredes Cotoré,
John D Potter,
Polly A Newcomb,
Michael N Passarelli,
Mark A Jenkins,
John L Hopper,
Steven Gallinger,
Loic Le Marchand,
María E Martínez,
Dennis J Ahnen,
John A Baron,
Noralane M Lindor, Robert W Haile,
Manuela Gago-Dominguez
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ABSTRACT: Recent genome-wide studies identified a risk locus for colorectal cancer at 18q21, which maps to the SMAD7 gene. Our objective was to confirm the association between SMAD7 SNPs and colorectal cancer risk in the multi-center Colon Cancer Family Registry.
23 tagging SNPs in the SMAD7 gene were genotyped among 1,592 population-based and 253 clinic-based families. The SNP-colorectal cancer associations were assessed in multivariable conditional logistic regression.
Among the population-based families, both SNPs rs12953717 (odds ratio, 1.29; 95% confidence interval, 1.12-1.49), and rs11874392 (odds ratio, 0.80; 95% confidence interval, 0.70-0.92) were associated with risk of colorectal cancer. These associations were similar among the population- and the clinic-based families, though they were significant only among the former. Marginally significant differences in the SNP-colorectal cancer associations were observed by use of nonsteroidal anti-inflammatory drugs, cigarette smoking, body mass index, and history of polyps.
SMAD7 SNPs were associated with colorectal cancer risk in the Colon Cancer Family Registry. There was evidence suggesting that the association between rs12953717 and colorectal cancer risk may be modified by factors such as smoking and use of nonsteroidal anti-inflammatory drugs.
PLoS ONE 01/2013; 8(4):e60464. · 4.09 Impact Factor
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Jennifer D Brooks,
Sharon N Teraoka,
Kathleen E Malone, Robert W Haile,
Leslie Bernstein,
Charles F Lynch,
Lene Mellemkjær,
David J Duggan,
Anne S Reiner,
Patrick Concannon,
Katherine Schiermeyer,
Juan Pablo Lewinger,
Jonine L Bernstein,
Jane C Figueiredo
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ABSTRACT: Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.
International Journal of Molecular Epidemiology and Genetics 01/2013; 4(1):35-48.
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Anne S Reiner,
Esther M John,
Jennifer D Brooks,
Charles F Lynch,
Leslie Bernstein,
Lene Mellemkjær,
Kathleen E Malone,
Julia A Knight,
Marinela Capanu,
Sharon N Teraoka,
Patrick Concannon,
Xiaolin Liang,
Jane C Figueiredo,
Susan A Smith,
Marilyn Stovall,
Malcolm C Pike, Robert W Haile,
Duncan C Thomas,
Colin B Begg,
Jonine L Bernstein
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ABSTRACT: PURPOSETo fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations. PATIENTS AND METHODS
From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.ResultsFamily history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%. CONCLUSION
Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.
Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
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Ulrike Peters,
Shuo Jiao,
Fredrick R Schumacher,
Carolyn M Hutter,
Aaron K Aragaki,
John A Baron,
Sonja I Berndt,
Stéphane Bézieau,
Hermann Brenner,
Katja Butterbach, [......],
Darin Taverna,
Stephen N Thibodeau,
Cornelia M Ulrich,
Emily White,
Yongbing Xiang,
Brent W Zanke,
Yi-Xin Zeng,
Ben Zhang,
Wei Zheng,
Li Hsu
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ABSTRACT: BACKGROUND & AIMS: Heritable factors contribute to development of colorectal cancer (CRC). Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis we identified a locus that reached the conventional genome-wide significance level at <5.0 x 10-8: an intergenic region on chromosome 2q32.3, close toNABP1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR]=1.15 per risk allele;P =3.7 x 10-8). We also found evidence for 3 additional loci with P values <5.0 x 10-7: a locus within theLAMC1gene on chromosome 1q25.3 (rs10911251; OR=1.10 per risk allele;P =9.5 x 10-8), a locus within theCCND2gene on chromosome 12p13.32 (rs3217810 per risk allele; OR=0.84;P =5.9 x 10-8), and a locus in theTBX3gene on chromosome 12q24.21 (rs59336, OR=0.91 per risk allele;P =3.7 x 10-7). CONCLUSIONS: In a large GWAS, we associated polymorphisms close toNABP (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms inLAMC1 (this is the second gene in the laminin family to be associated with CRCs),CCND2 (which encodes for cyclin D2), andTBX3 (which encodes a T-box transcription factor and is a target of Wnt signaling to -catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Gastroenterology 12/2012; · 11.68 Impact Factor
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James G Dowty,
Aung K Win,
Daniel D Buchanan,
Noralane M Lindor,
Finlay A Macrae,
Mark Clendenning,
Yoland C Antill,
Stephen N Thibodeau,
Graham Casey,
Steve Gallinger, [......],
Barbara A Leggett,
Michael Gattas,
Alex Boussioutas,
Dennis J Ahnen,
John A Baron,
Susan Parry,
Jack Goldblatt,
Joanne P Young,
John L Hopper,
Mark A Jenkins
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ABSTRACT: We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC) and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks to age 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (p<0.001), with cumulative risks to age 70 years estimated to follow U-shaped distributions. For example 17% of male MSH2 mutation carriers have estimated lifetime risks of 0-10% while 18% have risks of 90-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.
Human Mutation 12/2012; · 5.69 Impact Factor
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Jennifer D Brooks,
Leslie Bernstein,
Sharon N Teraoka,
Julia A Knight,
Lene Mellemkjaer,
Esther M John,
Kathleen E Malone,
Anne S Reiner,
Charles F Lynch,
Patrick Concannon, Robert W Haile,
Jonine L Bernstein
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation and altered levels of adipose derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight and weight change are associated with CBC risk. METHODS: Variants in twenty genes (182 single nucleotide polymorphisms) involved in adipose tissue metabolism, energy balance, insulin resistance and inflammation, as well as those identified through genome-wide association studies of BMI and type II diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants (643 cases with CBC and 1,271 controls with unilateral breast cancer) in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression. RESULTS: After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor status did not alter these findings. CONCLUSIONS: Among women with early onset disease who survive a first breast cancer diagnosis there was no association between variation in obesity-related genes and risk of CBC. Impact:Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.
Cancer Epidemiology Biomarkers & Prevention 10/2012; · 4.12 Impact Factor
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Anthony A Razzak,
Amy S Oxentenko,
Robert A Vierkant,
Lori S Tillmans,
Alice H Wang,
Daniel J Weisenberger,
Peter W Laird,
Charles F Lynch,
Kristin E Anderson,
Amy J French, Robert W Haile,
Lisa J Harnack,
John D Potter,
Susan L Slager,
Thomas C Smyrk,
Stephen N Thibodeau,
James R Cerhan,
Paul J Limburg
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ABSTRACT: Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.
Nutrition and Cancer 10/2012; 64(7):899-910. · 2.78 Impact Factor
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Bryony A Thompson,
David E Goldgar,
Carol Paterson,
Mark Clendenning,
Rhiannon Walters,
Sven Arnold,
Michael T Parsons,
D Michael,
Steven Gallinger, Robert W Haile,
John L Hopper,
Mark A Jenkins,
Loic Lemarchand,
Noralane M Lindor,
Polly A Newcomb,
Stephen N Thibodeau,
Joanne P Young,
Daniel D Buchanan,
Sean V Tavtigian,
Amanda B Spurdle
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ABSTRACT: Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ∼12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
Human Mutation 09/2012; · 5.69 Impact Factor
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Aung Ko Win,
Noralane M Lindor,
Joanne P Young,
Finlay A Macrae,
Graeme P Young,
Elizabeth Williamson,
Susan Parry,
Jack Goldblatt,
Lara Lipton,
Ingrid Winship, [......],
Mark Clendenning,
Christophe Rosty,
Julie Arnold,
A Joan Levine, Robert W Haile,
Steven Gallinger,
Loïc Le Marchand,
Polly A Newcomb,
John L Hopper,
Mark A Jenkins
[show abstract]
[hide abstract]
ABSTRACT: Background Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. Methods We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. Results Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). Conclusion Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
CancerSpectrum Knowledge Environment 08/2012; 104(18):1363-72. · 14.07 Impact Factor
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ABSTRACT: Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.
Human Genetics 06/2012; 131(10):1565-89. · 5.07 Impact Factor
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ABSTRACT: BACKGROUND: Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes (IGF1, IGF2, IGFBP1, IGFBP3, IRS1, and IRS2) and three genes associated with estrogen signaling (ESR1, ESR2, and PGR). METHODS: We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case-control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P (act). RESULTS: Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P (act) = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P (act) = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger (>1 cm) adenomas. CONCLUSIONS: These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.
International Journal of Colorectal Disease 05/2012; · 2.38 Impact Factor
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Jennifer D. Brooks,
Esther M. John,
Lene Mellemkjær,
Anne S. Reiner,
Kathleen E. Malone,
Charles F. Lynch,
Jane C. Figueiredo, Robert W. Haile,
Roy E. Shore,
The WECARE Study Collaborative Group,
Jonine L. Bernstein,
Leslie Bernstein
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ABSTRACT: The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help
reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between
body mass index (BMI) and CBC have yielded mixed results. From the population-based, case–control, Women’s Environmental,
Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast
cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were
used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change
between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However,
obese (BMI ≥30kg/m2) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n=12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI <25kg/m2) (n=43 cases and 98 controls) (RR=5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal
or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population
of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal
women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.
KeywordsBMI–Second primary contralateral breast cancer–ER-negative
Breast Cancer Research and Treatment 05/2012; 131(2):571-580. · 4.43 Impact Factor
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Aung K Win,
Sean P Cleary,
James G Dowty,
Noralane M Lindor,
Polly A Newcomb, Robert W Haile,
Joanne P Young,
Daniel D Buchanan,
Loïc Le Marchand,
Roger Green,
John L Hopper,
Steven Gallinger,
Mark A Jenkins
Hereditary Cancer in Clinical Practice 05/2012; 9:1-1. · 1.68 Impact Factor
