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1.
Am J Epidemiol ; 190(2): 230-238, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524116

RESUMO

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.

2.
Fam Cancer ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33464460

RESUMO

Lynch syndrome is the most frequent hereditary colorectal cancer (CRC) syndrome, affecting approximately 1 in 300 in the Western population. It is caused by pathogenic variants in the mismatch repair (MMR) genes including MLH1, MSH2 (EPCAM), MSH6 and PMS2, and is associated with high risks of CRC, endometrial cancer and other cancers. In view of these risks, carriers of such variants are encouraged to participate in colonoscopic surveillance programs that are known to substantially improve their prognosis. In the last decade several important studies have been published that provide detailed cancer risk estimates and prognoses based on large numbers of patients. These studies also provided new insights regarding the pathways of carcinogenesis in CRC, which appear to differ depending on the specific MMR gene defect. In this report, we will discuss the implications of these new findings for the development of new surveillance protocols.

3.
Fam Cancer ; 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33098072

RESUMO

BACKGROUND: Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient's prognosis. Recently, a network of physicians in Middle Eastern and North African (ME/NA) countries was established to improve the identification and management of LS families. The aim of the present survey was to evaluate current healthcare for families with LS in this region. METHODS: A questionnaire was developed that addressed the following issues: availability of clinical management guidelines for LS; attention paid to family history of cancer; availability of genetic services for identification and diagnosis of LS; and assessment of knowledge of LS surveillance. Members of the network and authors of recent papers on LS from ME/NA and neighbouring countries were invited to participate in the survey and complete the online questionnaire. RESULTS: A total of 55 individuals were invited and 19 respondents from twelve countries including Algeria, Azerbaijan, Cyprus, Egypt, Iran, Jordan, Kuwait, Lebanon, Morocco, Palestine, Tunisia, and Turkey completed the questionnaire. The results showed that family history of CRC is considered in less than half of the surveyed countries. Guidelines for the management of LS are available in three out of twelve countries. The identification and selection of families for genetic testing were based on clinical criteria (Amsterdam criteria II or Revised Bethesda criteria) in most countries, and only one country performed universal screening. In most of the surveyed countries genetic services were available in few hospitals or only in a research setting. However, surveillance of LS families was offered in the majority of countries and most frequently consisted of regular colonoscopy. CONCLUSION: The identification and management of LS in ME/NA countries are suboptimal and as a result most LS families in the region remain undetected. Future efforts should focus on increasing awareness of LS amongst both the general population and doctors, and on the improvement of the infrastructure in these countries.

4.
Cancer Epidemiol ; 69: 101809, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32947154

RESUMO

BACKGROUND: Persons with Lynch syndrome (LS) have an increased risk of developing colorectal tumors (CRTs). Adherence to diet quality indices associated with colorectal cancer (CRC) risk in the general population has not been studied before in LS. METHODS: Dietary habits of 490 participants with LS from a prospective cohort study was collected using a food frequency questionnaire. The Dutch Healthy Diet index 2015 (DHD15-index) and Dietary Approaches to Stop Hypertension (DASH) were used to score food-based diet quality. Diet quality scores were divided into tertiles where a higher tertile reflects a higher diet quality. Multivariable Cox proportional hazard regression models were used to estimate the association between the DHD15-index, DASH score and CRT risk. RESULTS: During a median follow-up time of 53.4 months, 210 participants (42.9%) developed CRTs. The DHD-index and DASH score were not associated with CRT risk; hazard ratios for highest vs. lowest tertile were 1.00 (95% Confidence Interval (CI): 0.67-1.48) and 1.11 (95% CI: 0.74-1.69), respectively. No linear trends across the DHD-index and DASH score tertiles were observed (P-trend = 0.97 and 0.83 respectively). CONCLUSION: In contrast to observations in the general population, no evidence for an association between the food-based DHD15-index or DASH score and CRT risk was observed in persons with LS. Further studies are needed investigating the association between diet quality and mechanisms leading to the development of LS-associated tumors.

5.
Am J Epidemiol ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32803246

RESUMO

Persons with Lynch syndrome (LS - carrying a pathogenic mutation in a DNA mismatch repair gene) have an increased colorectal cancer (CRC) and endometrial cancer (EC) risk. A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for LS. We aimed to investigate the association between height and CRC and EC for persons with LS using two large studies. Information of 1,213 men and 1,636 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch cohort study (2006-2017) was harmonized. We used weighted Cox proportional hazard regression models with age on the time-axis to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for each 5 cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation and 171 women were diagnosed with EC during 39,227 person-years of observation. Height was not associated with CRC for men (HR 1.00 per 5 cm, 95%CI: 0.91, 1.11) or women (HR 1.01 per 5 cm, 95%CI: 0.92, 1.11). Nor was height associated with EC (HR 1.08 per 5 cm, 95%CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC for persons with LS.

6.
Fam Cancer ; 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770331

RESUMO

A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch study, a prospective cohort study. Information on dietary intake and lifestyle habits was collected with a validated semi-quantitative food frequency questionnaire and a general questionnaire administered at baseline (2006-2008) and follow-up (2012-2017). Participants' medical records were used to identify CRN diagnoses. Changes in dietary and lifestyle habits in the CRN and the no-CRN group were compared using multivariable linear regression models for continuous variables and cross-tables with percentage change at follow-up compared with baseline for categorical variables. Of the 324 included participants, 146 developed a CRN (CRN group) between baseline and follow-up, while 178 did not (no-CRN group). Smoking cessation was more often reported in the CRN than in the no-CRN group (41.4% vs. 35.0%). There were no differences in changes of energy intake, alcohol, red meat, processed meat, dairy, fruit, vegetables and dietary fiber consumption, BMI, physical activity and NSAID use. Apart from a potentially higher likelihood of smoking cessation, we found little evidence that a CRN diagnosis is associated with changes in lifestyle habits in persons with LS.

7.
BMC Gastroenterol ; 20(1): 225, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660488

RESUMO

BACKGROUND: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. METHODS: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. DISCUSSION: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. TRIAL REGISTRATION: Netherlands Trial Register, NL7083 , 06 July 2018.

8.
J Med Genet ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32482799

RESUMO

BACKGROUND: Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants. METHODS: Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families. RESULTS: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%). CONCLUSIONS: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.

9.
Psychooncology ; 29(6): 1084-1091, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32237002

RESUMO

OBJECTIVE: This study aimed to assess psychological functioning, quality of life, and regret about screening after a positive fecal immunochemical test (FIT) and subsequent colonoscopy, and to evaluate changes over time. METHODS: This is a prospective cohort study. Individuals aged 55 to 75 with a positive FIT that were referred for colonoscopy between July 2017 and November 2018, were invited to complete questionnaires related to psychological distress and health-related quality of life at three predefined time points: before colonoscopy, after histopathology result notification, and after 6 months. Four questionnaires were used: the Psychological Consequences Questionnaire (PCQ), the six-item Cancer Worry Scale (CWS), the Decision Regret Scale (DRS), and the 36-item Short-Form (SF-36). RESULTS: A total of 1066 participants out of 2151 eligible individuals were included. Patients with cancer showed a significant increase in psychological dysfunction (P = .01) and cancer worry (P = .008) after colonoscopy result notification, and a decline to pre-colonoscopy measurements after 6 months. In the no-cancer groups, psychological dysfunction and cancer worry significantly decreased over time (P < .05) but there was no ongoing decline. After 6 months, 17% of participants with no cancer experienced high level of cancer worry (CWS ≥ 10). Yet, only 5% reported high level of regret about screening participation (DRS > 25). A good global quality of life was reported in participants with no cancer. CONCLUSION: Some psychological distress remains up to 6 months after colonoscopy in participants who tested false-positive in the Dutch bowel cancer screening program.

10.
Fam Cancer ; 19(2): 183-187, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088803

RESUMO

Barrett's oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1-72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE.

11.
Eur J Hum Genet ; 28(2): 222-230, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31527860

RESUMO

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged <60 and >20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRAS c.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged <60 and with >20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing.

12.
Gut ; 69(1): 7-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672839

RESUMO

BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions. CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.


Assuntos
Carcinoma/diagnóstico , Detecção Precoce de Câncer/métodos , Neoplasias Pancreáticas/diagnóstico , Fatores Etários , Pesquisa Biomédica/métodos , Carcinoma/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Programas de Rastreamento/métodos , Neoplasias Pancreáticas/genética , Vigilância da População/métodos , Fatores de Risco
13.
Scand J Gastroenterol ; 54(6): 733-739, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31401889

RESUMO

Background: Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of colorectal adenomas in the second decade of life, and prophylactic colectomy is usually performed around age of 20. A common question is the appropriate timing of surgery and which endoscopic findings indicate surgery. Methods: All FAP patients known at Leiden University Medical Centre from 1985 onwards were included. The patients were then subdivided into those diagnosed before or after 2000. Patient information included age at diagnosis, colonic phenotype, age at surgery, pathological findings and the outcome of follow-up colonoscopies in whom surgery was postponed. Results: The 72 FAP patients identified consisted of 33 patients diagnosed before (group A) and 39 after (group B) 2000. The median age at diagnosis for patients with classical FAP was 18 in groups A and B. All patients diagnosed before 2000 underwent colorectal surgery versus 68% of those diagnosed >2000. The median age at surgery for classical FAP patients was 19 and 24 years in groups A and B, respectively. In patients with intact colon, the number of adenomas gradually increased over many years. Although most adenomas remained <5 mm, the proportion of 5-15 mm adenomas slowly increased. Only one patient developed a high-grade adenoma. None of the patients developed CRC. Conclusions: Surgery today in FAP is performed less often and at a more advanced age. Our experience also suggests that surgery can be safely postponed in selected patients. The most important endoscopic indication for surgery is substantial number of large adenomas of >5-10 mm.


Assuntos
Adenoma/patologia , Polipose Adenomatosa do Colo/cirurgia , Neoplasias Colorretais/patologia , Cirurgia Colorretal , Adolescente , Adulto , Criança , Bases de Dados Factuais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
14.
J Med Genet ; 56(9): 581-589, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186341

RESUMO

BACKGROUND: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. METHODS: 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. RESULTS: The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. CONCLUSION: Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Estudos de Casos e Controles , Tomada de Decisão Clínica , Gerenciamento Clínico , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Adulto Jovem
15.
Fam Cancer ; 18(3): 349-352, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31111311

RESUMO

Subtotal colectomy is usually the therapy of choice in Lynch syndrome patients diagnosed with colon cancer. In patients who develop cancer after the age of 50-60 years, segmental colectomy is considered a good alternative. Although the endoscopic treatment of early colorectal cancer in non-Lynch patients has increased in the last decades, almost all patients with a Lynch syndrome-associated colorectal malignancy undergo surgery, even if the tumour is diagnosed in a (very) early stage. One of the endoscopic treatment options for early colorectal cancer is an endoscopic full thickness resection (eFTR). This treatment modality allows optimal pathological examination of the resection specimen, as a transmural resection is performed with optimal T-staging of the tumour. We report a case of a 62 year old man, diagnosed with MSH2-Lynch syndrome, who underwent successful eFTR treatment of an early (pT1) colon cancer located in the ascending colon, with no signs of recurrence 12 months after treatment. We discuss the pros and cons of endoscopic resection of early colorectal carcinoma in Lynch syndrome patients.


Assuntos
Neoplasias do Colo/cirurgia , Colonoscopia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/cirurgia , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Carcinoma/genética , Carcinoma/cirurgia , Colo Ascendente/cirurgia , Neoplasias do Colo/patologia , Colonoscopia/instrumentação , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Detecção Precoce de Câncer , Humanos , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia
16.
HPB (Oxford) ; 21(10): 1371-1375, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30910317

RESUMO

BACKGROUND: MRI surveillance in a cohort of CDKN2A-p16-Leiden mutation carriers with a 20% lifetime risk of PDAC led to increased resection rates and improved survival. Patients with screen-detected PDAC were evaluated for main pancreatic duct (MPD) abnormalities in this retrospective review. METHODS: Since 2000 annual MRI and optional EUS was performed in mutation carriers. Data of patients with screen-detected PDAC was collected on gender, age at diagnosis, site of tumor, size, outcome of surgery, pathology findings and survival. All MRIs were re-evaluated for MPD abnormalities. RESULTS: 23 PDAC were detected in 22 (10%) of 217 mutation carriers, 10 (45%) males and 12 (55%) females. The mean age at diagnosis was 59.8 years (range 39.2-74.3 years). Revision of the MRI/MRCP revealed a lesion and dilatation of the MPD in 8 of the 22 patients. In 5 of 7 patients with PDAC detected during follow-up, the previous MRI showed MPD dilatation without evidence of tumor. The mean size of PDAC was 12.3 mm (range 5-19 mm). All tumors were resectable. CONCLUSION: MPD dilation is common in patients with screen-detected PDAC. Abnormalities on MRI during surveillance of high-risk individuals requires intense follow-up or prompt treatment, as early treatment results in a better prognosis.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Carcinoma/diagnóstico , Dilatação Patológica/patologia , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
18.
Mol Genet Genomic Med ; 7(4): e00603, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827058

RESUMO

BACKGROUND: Germline mutations affecting the exonuclease domains of POLE and POLD1 predispose to colorectal adenomas and carcinoma. Here, we aimed to screen the exonuclease domains to find the genetic causes of multiple colorectal polyps in unexplained cases. METHODS: Using a custom next-generation sequencing panel, we sequenced the exonuclease domains of POLE and POLD1 in 332 index patients diagnosed with multiple colorectal polyps without germline alteration in colorectal polyposis predisposing genes. RESULTS: We identified two variants of unknown significance. One germline POLD1 c.961G>A, p.(Gly321Ser) variant was found in two cases. The first patient was diagnosed with multiple polyps at age 35 and colorectal cancer (CRC) at age 37, with no known family history of CRC. The second patient was diagnosed with CRC at age 44 and cumulatively developed multiple polyps; this patient had two sisters with endometrial cancer who did not carry the variant. Furthermore, we identified a novel POLD1 c.955 T>G, p.(Cys319Gly) variant in a patient diagnosed with multiple colorectal adenomas at age 40. Co-segregation analysis showed that one sister who cumulatively developed multiple adenomas from age 34, and another sister who developed CRC at age 38 did not carry the variant. We did not identify pathogenic variants in POLE and POLD1. CONCLUSION: This study confirms the low frequency of causal variants in these genes in the predisposition for multiple colorectal polyps, and also establishes that these genes are a rare cause of the disease.


Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Taxa de Mutação , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Domínio Catalítico , DNA Polimerase II/química , DNA Polimerase III/química , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas de Ligação a Poli-ADP-Ribose/química
19.
J Clin Oncol ; 36(29): 2961-2968, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30161022

RESUMO

PURPOSE: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. METHODS: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. RESULTS: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. CONCLUSION: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Neoplasias/epidemiologia , Neoplasias/genética , Penetrância , Adulto , Idoso , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
20.
Cancer Prev Res (Phila) ; 11(9): 551-556, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29991580

RESUMO

CDKN2A-p16-Leiden mutation carriers have a 20% to 25% risk of developing pancreatic ductal adenocarcinoma (PDAC). Better understanding of the natural course of PDAC might allow the surveillance protocol to be improved. The aims of the study were to evaluate the role of cystic precursor lesions in the development of PDAC and to assess the growth rate. In 2000, a surveillance program was initiated, consisting of annual MRI in carriers of a CDKN2A-p16-Leiden mutation. The study cohort included 204 (42% male) patients. Cystic precursor lesions were found in 52 (25%) of 204 mutation carriers. Five (9.7%) of 52 mutation carriers with cystic lesions and 8 (7.0%) of 114 mutation carriers without cystic lesions developed PDAC (P = 0.56). Three of 6 patients with a cystic lesion of ≥10 mm developed PDAC. The median size of all incident PDAC detected between 9 and 12 months since the previous normal MRI was 15 mm, suggesting an annual growth rate of about 15 mm/year. In conclusion, our findings show that patients with and without a cystic lesions have a similar risk of PDAC. However, cystic precursor lesions between 10 and 20 mm increase the risk of PDAC substantially. In view of the large size of the screen-detected tumors, a shorter interval of screening might be recommended for all patients. Cancer Prev Res; 11(9); 551-6. ©2018 AACR.


Assuntos
Carcinoma Ductal Pancreático/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Cisto Pancreático/genética , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Adulto , Idoso , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Seguimentos , Efeito Fundador , Predisposição Genética para Doença , Heterozigoto , Humanos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/epidemiologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/epidemiologia , Lesões Pré-Cancerosas/patologia , Fatores de Tempo
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