Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and
) account for some familial aggregation of colorectal cancer, their population prevalence and the ...causes of the remaining familial aggregation are not known.
We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and
We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.
We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (
= 1 in 1,946,
= 1 in 2,841,
= 1 in 758,
= 1 in 714), 1 in 45 carry mutations in
, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).
Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.
Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.
.
Increased Cancer Risks in Myotonic Dystrophy Win, Aung Ko, MBBS, MPH; Perattur, Promilla G., MBBS; Pulido, Jose S., MD, MS, MPH, MBA ...
Mayo Clinic proceedings,
02/2012, Letnik:
87, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract Objective To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested ...in several studies but the risks of cancers have not been quantified. Patients and Methods A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method. Results A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval CI, 1.80-12.93; P =.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P <.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P =.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P =.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma. Conclusion Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers.
It has been controversial that men carrying a DNA mismatch repair (MMR) gene mutation (Lynch syndrome) are at heightened risk of prostate cancer given that an increased risk is likely to be modest ...and the prevalence of prostate cancer is high. We used PubMed to search for "molecular studies" that reported MMR-deficiency status of prostate cancer tumors in men with an MMR gene mutation, and "risk studies" that reported prostate cancer risk for men known or suspected to have an MMR gene mutation relative to that for noncarriers or the general population. Of the six molecular studies, 32 of 44 73%, 95% confidence intervals (CI), 57%-85% prostate cancer tumors in carriers were MMR deficient, which equates to carriers having a 3.67-fold increased risk of prostate cancer (95% CI, 2.32-6.67). Of the 12 risk studies, we estimated a 2.13-fold increased risk of prostate cancer (95% CI, 1.45-2.80) for male carriers in clinic-based retrospective cohorts, 2.11 (95% CI, 1.27-2.95) for male carriers with a prior diagnosis of colorectal cancer, and 2.28 (95% CI, 1.37-3.19) for all men from mutation-carrying families. The combination of evidence from molecular and risk studies in the current literature supports consideration of prostate cancer as part of Lynch syndrome.
In December 2019, the COVID-19 disease started in Wuhan, China. The WHO declared a pandemic on 12 March 2020, and the disease started in Myanmar on 23 March 2020. In December 2020, different variants ...were brought worldwide, threatening global health. To counter those threats, Myanmar started the COVID-19 variant surveillance program in late 2020. Whole genome sequencing was done six times between January 2021 and March 2022. Among them, 83 samples with a PCR threshold cycle of less than 25 were chosen. Then, we used MiSeq FGx for sequencing and Illumina DRAGEN COVIDSeq pipeline, command line interface, GISAID, and MEGA version 7 for data analysis. In January 2021, no variant was detected. The second run, during the rise of cases in June 2021, showed Alpha, Delta, and Kappa variants. The third and the fourth runs in August and December showed only a Delta variant. Omicron and Delta variants were detected during the fifth run in January 2022. The sixth run in March 2022 showed only Omicron BA.2. Amino acid mutation at the receptor binding domain of Spike glycoprotein started since the second run coupling with high transmission, recurrence, and vaccine escape. We also found the mutation at the primer targets used in current RT-PCR platforms, but there was no mutation at the existing antiviral drug targets. The occurrence of multiple variants and mutations claimed vigilance at ports of entry and preparedness for effective control measures. Genomic surveillance with the observation of evolutionary data is required to predict imminent threats of the current disease and diagnose emerging infectious diseases.
Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden ...of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.
Using the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.
We identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13).
Since breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.
Non‐melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer occurring in people with fair skin. Australia has been reported to ...have the highest incidence of NMSC in the world. Using a systematic search of the literature in EMBASE and Medline, we identified 21 studies that investigated the incidence or prevalence of NMSC in Australia. Studies published between 1948 and 2011 were identified and included in the analysis. There were six studies that were conducted on national level, two at state level and 13 at the regional level. Overall, the incidence of NMSC had steadily increased over calendar‐years in Australia. The incidence of NMSC per 100 000 person‐years was estimated to be 555 in 1985; 977 in 1990; 1109 in 1995; 1170 in 2002 and 2448 in 2011. The incidence was higher for men than women and higher for BCC than SCC. Incidence varied across the states of Australia, with the highest in Queensland. The prevalence of NMSC was estimated to be 2% in Australia in 2002. The incidence and prevalence of NMSC still need to be accurately established at both national and state levels to determine the costs and burden of the disease on the public health system in Australia.
Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer ‐ metachronous CRC. Understanding which pathological features of the first tumour are associated with ...risk of metachronous CRC might help tailor existing surveillance guidelines. Population‐based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow‐up time of 12 years (incidence: 2.0 per 1000 person‐years). CRC cases with a synchronous CRC were 3.4‐fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89–5.98) than those without a synchronous tumour. CRC cases with MMR‐deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11–2.64) compared to those with MMR‐proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06–0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR‐deficient.
What's new?
Metachronous colorectal cancer (CRC), in which a second primary cancer occurs in the colon or rectum, affects a significant proportion of CRC survivors. Here, the authors investigated relationships in pathology between initial CRC and metachronous CRC. After exclusion of CRC due to Lynch syndrome, patients whose cancer was mismatch repair (MMR)‐deficient or was synchronous with another instance of CRC at diagnosis were found to have a 3.4‐fold and 1.7‐fold increase in risk of metachronous CRC, respectively. The findings suggest that inclusion of MMR deficiency and synchronous CRC in surveillance measures could help improve early detection of metachronous CRC.
Abstract
Background
Identifying risk factors for metachronous colorectal cancer (CRC) and metachronous advanced neoplasia could be useful for guiding surveillance. We conducted a systematic review ...and meta-analysis to investigate risk factors for metachronous CRC and advanced neoplasia.
Methods
Searches were conducted in MEDLINE, Embase, Web of Science and Cochrane Central Registry of Controlled Trials for articles (searching period: 1945 to Feburary, 2021) that reported the results of an association between any factor and metachronous advanced neoplasia or metachronous CRC. There were no restrictions on the publication date or language. Random effects models were fitted to estimate the combined association between the risk factors and metachronous CRC or advanced neoplasia. The Risk of Bias In Non-Randomised Studies of Interventions tool (ROBINS-I) was used to assess the risk of bias of included studies.
Results
In total, 22 observational studies with 625,208 participants were included in the systematic review and meta-analysis. Of these, 13 studies investigated risk factors for metachronous CRC and 9 for advanced neoplasia. The risks of metachronous CRC or advanced neoplasia were higher if the first CRC was diagnosed in the presence of a synchronous advanced lesion (pooled risk ratio (RR) from 3 studies: 3.61, 95% confidence interval (CI): 1.44–9.05; and pooled RR from 8 studies: 2.77, 95% CI: 2.23–3.43, respectively). The risk of metachronous CRC was lower, but the risk of metachronous advanced neoplasia was higher if the first CRC was distal (compared with proximal) (pooled RR from 3 studies: 0.48, 95% CI: 0.23–0.98; and pooled RR from 2 studies: 2.99, 95% CI: 1.60–5.58 respectively). The risk of metachronous advanced neoplasia increased with age (pooled RR from 3 studies: 1.07 per year of age, 95% CI: 1.03–1.11). There was no evidence that any lifestyle risk factors studied were associated with the risk of metachronous CRC or advanced neoplasia.
Conclusions
The identified risk factors for metachronous CRC and advanced neoplasia might be useful to tailor the existing surveillance guidelines after the first CRC. There were potential limitations due to possible misclassification of the outcome, confounding and risk of bias, and the findings cannot be generalised to high-risk genetic syndrome cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol ...consumption and colorectal cancer risk have been inconclusive.
1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer.
Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and >28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09-2.07 and 1.69; 95% CI, 1.07-2.65, respectively;
= 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27-2.49 and 1.94; 95% CI, 1.19-3.18, respectively;
= 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk.
Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (∼2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers.
Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk.
.
Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene
underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the ...robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.
Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic
germline PV carriers, 25 sporadic
methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.
The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic
carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific
variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10
), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.
Assessment of SBS and ID signatures can discriminate CRCs from biallelic
carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
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