Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

Gut ◽  
2016 ◽  
Vol 67 (3) ◽  
pp. 447-455 ◽  
Author(s):  
Lisanne S Rigter ◽  
Petur Snaebjornsson ◽  
Efraim H Rosenberg ◽  
Peggy N Atmodimedjo ◽  
Berthe M Aleman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
General Population ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Hodgkin’S Lymphoma ◽  
Gene Mutations ◽  
Hodgkin's Lymphoma ◽  
Molecular Characteristics ◽  
Increased Risk ◽  
General Population Cohort

ObjectiveHodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.Design54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).ResultsKRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.ConclusionsWe have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.

scholarly journals Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project

2017 ◽  
Vol 76 (12) ◽  
pp. 2025-2030 ◽  
Author(s):  
Louise K Mercer ◽  
Anne C Regierer ◽  
Xavier Mariette ◽  
William G Dixon ◽  
Eva Baecklund ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
General Population ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Treatment Groups ◽  
Increased Risk

BackgroundLymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes.MethodsPatients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD.ResultsAmong 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population.ConclusionThis large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

scholarly journals Endocrine and Metabolic Diseases Among Colorectal Cancer Survivors in a Population-Based Cohort

2019 ◽  
Vol 112 (1) ◽  
pp. 78-86
Author(s):  
Makenzie L Hawkins ◽  
Brenna E Blackburn ◽  
Kerry Rowe ◽  
John Snyder ◽  
Vikrant G Deshmukh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factor ◽  
General Population ◽  
Metabolic Diseases ◽  
The United States ◽  
Population Cohort ◽  
Increased Risk ◽  
General Population Cohort ◽  
Time Periods

Abstract Background There are an estimated 1.4 million colorectal cancer (CRC) survivors in the United States. Research on endocrine and metabolic diseases over the long term in CRC survivors is limited. Obesity is a risk factor for CRC; thus it is of interest to investigate diseases that may share this risk factor, such as diabetes, for long-term health outcomes among CRC survivors. Methods A total of 7114 CRC patients were identified from the Utah Population Database and matched to a general population cohort of 25 979 individuals on birth year, sex, and birth state. Disease diagnoses (assessed over three time periods of 1–5 years, 5–10 years, and &gt;10 years) were identified using electronic medical records and statewide ambulatory and inpatient discharge data. Cox proportional hazard models were used to estimate the risk of endocrine and metabolic disease. Results Across all three time periods, risks for endocrine and metabolic diseases were statistically significantly greater for CRC survivors compared with the general population cohort. At 1–5 years postdiagnosis, CRC survivors’ risk for diabetes mellitus with complications was statistically significantly elevated (hazard ratio [HR] = 1.36, 99% confidence interval [CI] = 1.09 to 1.70). CRC survivors also experienced a 40% increased risk of obesity at 1–5 years postcancer diagnosis (HR= 1.40, 99% CI= 1.66 to 2.18) and a 50% increased risk at 5–10 years postdiagnosis (HR = 1.50, 99% CI= 1.16 to 1.95). Conclusions Endocrine and metabolic diseases were statistically significantly higher in CRC survivors throughout the follow-up periods of 1–5 years, 5–10 years, and more than 10 years postdiagnosis. As the number of CRC survivors increases, understanding the long-term trajectory is critical for improved survivorship care.

scholarly journals Frequency of germline hereditary non-polyposis colorectal cancer gene mutations in patients with multiple or early onset colorectal adenomas

Gut ◽  
1997 ◽  
Vol 41 (2) ◽  
pp. 235-238 ◽  
Author(s):  
N E Beck ◽  
I P M Tomlinson ◽  
T F R Homfray ◽  
I M Frayling ◽  
S V Hodgson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
General Population ◽  
Mismatch Repair ◽  
Gene Mutations ◽  
Single Strand Conformation Polymorphism ◽  
Germline Mutations ◽  
Colorectal Adenomas ◽  
Polymorphism Analysis ◽  
Predisposing Genes ◽  
Apc Mutations

Background—The hereditary non-polyposis colorectal cancer (HNPCC) syndrome is caused by germline mutations in mismatch repair genes and predisposes individuals to cancers of the colon and other specific sites. On theoretical grounds, it is expected that patients with HNPCC also develop more colorectal adenomas than the general population. In essence, if the mutation rate is raised owing to mutations at a mismatch repair locus, more mutations are expected at loci such as APC (adenomatous polyposis coli) and more adenomas will start to grow. Not all data support this expectation, however.Aim—To search for germline mutations at HNPCC loci in patients with multiple adenomas.Subjects—Twenty five patients (without known APC mutations) who have developed colorectal adenomas in unusually large numbers and, in some cases, at an early age.Methods—Germline APC mutations were excluded using the protein truction test for exon 15 and mismatch chemical cleavage analysis for remaining exons. Germline HNPCC mutations were detected by using PCR and single strand conformation polymorphism analysis.Results—Just one germline HNPCC mutation was found (4% of cases) and this was of uncertain functional effect.Conclusions—In general, germline HNPCC mutations are not responsible for the phenotype of patients with multiple colonic adenomas. It is possible that patients with HNPCC tend to develop adenomas more frequently and earlier than the general population, but that this effect is relatively subtle. These results suggest that individuals with colorectal adenomas only should not strictly be classified as “affected” in HNPCC families (although they should certainly not be classified as “unaffected” either and may warrant intensive screening). In the absence of a personal or strong family history of colorectal cancer, it is probably not worthwhile performing diagnostic or predictive genetic testing for HNPCC mutations in subjects with colorectal adenomas. Although undetected APC mutations may be responsible for some of the phenotypes in this sample, as yet uncharacterised adenoma predisposing genes probably exist.

Long-Term Solid Cancer Risk Among 5-Year Survivors of Hodgkin's Lymphoma

2007 ◽  
Vol 25 (12) ◽  
pp. 1489-1497 ◽  
Author(s):  
David C. Hodgson ◽  
Ethel S. Gilbert ◽  
Graça M. Dores ◽  
Sara J. Schonfeld ◽  
Charles F. Lynch ◽  
...  
Keyword(s):  
General Population ◽  
Hodgkin’S Lymphoma ◽  
Absolute Risk ◽  
Cancer Registries ◽  
Population Based ◽  
Hodgkin's Lymphoma ◽  
Solid Cancer ◽  
Increased Risk ◽  
Screening Strategies ◽  
Cumulative Risks

Purpose Hodgkin's lymphoma (HL) survivors are known to be at substantially increased risk of solid cancers (SC). However, no investigation has used multivariate modeling to estimate the relative risk (RR), excess absolute risk (EAR), and cumulative incidence for specific attained ages and ages at HL diagnosis. Patients and Methods We identified 18,862 5-year HL survivors from 13 population-based cancer registries in North America and Europe. Poisson regression was used to evaluate the effects of age at diagnosis, attained age, latency, sex, treatment, and year of diagnosis on the RR and EAR of SC. Results Among 1,490 identified SC, 850 were estimated to be in excess. For most cancer sites, both RR and EAR decreased with age at HL diagnosis and showed strong dependencies on attained age. For a patient diagnosed at age 30 years and survived to ≥ 40 years, modeled risks were significantly elevated for cancers of the breast (RR = 6.1), other supradiaphragmatic sites (RR = 6.0), and infradiaphragmatic sites (RR = 3.7); the largest RR (20-fold) was observed for malignant mesothelioma. Thirty-year cumulative risks of SC for men and women diagnosed at 30 years were 18% and 26%, respectively, compared with 7% and 9%, respectively, in the general population. For young HL patients, risks of breast and colorectal cancers were elevated 10 to 25 years before the age when routine screening would be recommended in the general population. Conclusion Multivariable modeling demonstrates for the first time temporal changes in SC risk not evident in unadjusted analyses, and can facilitate the development of individualized risk assessment and the creation of screening strategies for early detection.

scholarly journals Histomorphology and Molecular Genetics in Different Intra-Tumoral Zones and Matched Metastatic Lymph Nodes of Colorectal Cancer with Heterogenous Mismatch Repair Status

2021 ◽  
Author(s):  
Jing Zhang ◽  
Xin Zhang ◽  
Qian Wang ◽  
Yuyin Xu ◽  
Qianlan Yao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Lymph Nodes ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Gene Mutations ◽  
Metastatic Lymph Nodes ◽  
Molecular Alterations ◽  
Metastatic Lymph

Abstract Objective: To better understand the clinicopathological characteristics and molecular alterations in different intra-tumoral components of colorectal cancer (CRC) with heterogeneity of mismatch repair (MMR) protein expression and microsatellite instability (MSI) status.Methods: We identified 4 cases of CRC with heterogenous MMR protein expression and analyzed the histopathological features, MSI status and other molecular alterations in separately microdissected intra-tumoral zones and lymph node metastases by polymerase chain reaction (PCR) -based MSI testing, MLH1 promoter methylation and targeted next-generation sequencing (NGS).Results: Microsatellite instability-high (MSI-H) was identified in the MLH1/PMS2 deficient zones in Case 1-3, and in the MSH2/MSH6 deficient zone in Case 4, while MSS was in all the intra-tumoral zones and metastatic lymph nodes with proficient MMR (pMMR). Furthermore, heterogeneity of MLH1 promoter methylation and/or other common driving gene mutations of CRC, such as KRAS, PIK3CA and so on, was identified in all the 4 CRCs. In addition, 75% (3/4) of cases showed heterogeneity of histomorphology in intra-tumoral components and metastatic lymph nodes (Case 1, 2, 4), and all the corresponding metastatic lymph nodes were moderate differentiation with MSS/pMMR (Case 2, 3). Conclusions: The heterogeneous MSI status is highly correlated with histomorphological heterogeneity, which is also an important clue for the heterogeneity of drive gene mutations in CRC. These results suggest that it is essential to detect MMR protein expression and other gene mutations in metastases before treatment, especially for the CRCs with heterogenous MMR protein expression or histomorphology.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals Surveillance of Colorectal Cancer (CRC) in Cystic Fibrosis (CF) Patients

2021 ◽  
Vol 3 (2) ◽  
pp. 84-95
Author(s):  
Fabio Ingravalle ◽  
Giovanni Casella ◽  
Adriana Ingravalle ◽  
Claudio Monti ◽  
Federica De Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cystic Fibrosis ◽  
General Population ◽  
Genetic Disorder ◽  
The United States ◽  
Screening Colonoscopy ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Increased Risk ◽  
Speciality Training

Cystic Fibrosis (CF) is the commonest inherited genetic disorder in Caucasians due to a mutation in the gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), and it should be considered as an Inherited Colorectal Cancer (CRC) Syndrome. In the United States, physicians of CF Foundation established the “Developing Innovative Gastroenterology Speciality Training Program” to increase the research on CF in gastrointestinal and hepatobiliary diseases. The risk to develop a CRC is 5–10 times higher in CF patients than in the general population and even greater in CF patients receiving immunosuppressive therapy due to organ transplantation (30-fold increased risk relative to the general population). Colonoscopy should be considered the best screening for CRC in CF patients. The screening colonoscopy should be started at the age of 40 in CF patients and, if negative, a new colonoscopy should be performed every 5 years and every 3 years if adenomas are detected. For transplanted CF patients, the screening colonoscopy could be started at the age of 35, in transplanted patients at the age of 30 and, if before, at the age of 30. CF transplanted patients, between the age of 35 and 55, must repeat colonoscopy every 3 years. Our review draws attention towards the clinically relevant development of CRC in CF patients, and it may pave the way for further screenings and studies.

AIDS-Related Malignancies: State of the Art and Therapeutic Challenges

2008 ◽  
Vol 26 (29) ◽  
pp. 4834-4842 ◽  
Author(s):  
Jean-Philippe Spano ◽  
Dominique Costagliola ◽  
Christine Katlama ◽  
Nicolas Mounier ◽  
Eric Oksenhendler ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Hodgkin’S Lymphoma ◽  
Advanced Disease ◽  
State Of The Art ◽  
Hodgkin's Lymphoma ◽  
Increased Risk ◽  
Therapeutic Recommendations ◽  
The Subject ◽  
The Impact ◽  
Related Mortality

Despite the impact of combination antiretroviral therapy (cART) on HIV-related mortality, malignancy remains an important cause of death in the current era. Although the advent of cART has resulted in reductions in the incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma, non–AIDS-defining malignancies present an increased risk for HIV-infected patients, characterized by some common clinical features, generally with a more aggressive behavior and a more advanced disease at diagnosis, which is responsible for poorer patient outcomes. Specific therapeutic recommendations are lacking for these new nonopportunistic malignancies, such as Hodgkin's lymphoma, anal cancer, lung cancer, hepatocarcinoma, and many others. Antiretroviral agents have a propensity for causing drug interactions as a result of their ability to either inhibit or induce the cytochrome P450 (CYP) enzyme system. Because many antineoplastic drugs are also metabolized by the CYP system, coadministration with cART could result in either drug accumulation with increased toxicity, or decreased efficacy of one or both classes of drugs. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary. Special considerations of these AIDS-related and non–AIDS-related malignancies and their clinical and therapeutic aspects constitute the subject of this review.

scholarly journals Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort

2019 ◽  
Vol 40 (33) ◽  
pp. 2813-2824 ◽  
Author(s):  
Katrine L Rasmussen ◽  
Anne Tybjærg-Hansen ◽  
Børge G Nordestgaard ◽  
Ruth Frikke-Schmidt
Keyword(s):  
General Population ◽  
Cardiovascular Mortality ◽  
Cancer Mortality ◽  
Plasma Levels ◽  
Apoe Genotype ◽  
High Plasma ◽  
Increased Risk ◽  
Specific Mortality ◽  
General Population Cohort ◽  
Low Levels

Abstract Aims To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. Methods and results Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01–2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality. Conclusion High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.

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