Publications by authors named "Renee Perrier"

15 Publications

  • Page 1 of 1

Bilateral Nephroblastic Tumors and a Complex Renal Vascular Anomaly in a Patient With a Mosaic RASopathy: Novel Histopathologic Features and Molecular Insights.

Pediatr Dev Pathol 2021 May-Jun;24(3):235-240. Epub 2021 Feb 4.

Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Mosaic RASopathies are an emerging group of disorders characterized by mosaic or post-zygotic activating mutations in genes of the RAS/MAPKinase signaling pathway. The phenotype is highly variable, ranging from limited or localized forms to cases with a syndromic presentation with extensive or multiorgan involvement, and also overlaps with other mosaic disorders. While there are several reports of malignancies in patients with mosaic RASopathies, specifically rhabdomyosarcoma and transitional urothelial carcinoma, the lifetime risk and molecular mechanisms that lead to the development of malignancies remain unclear. We report a 22-month-old boy with a somatic RASopathy due to an underlying p.G12D mutation who presented with a large unilateral epidermal nevus, asymmetric lower limb overgrowth with lytic and sclerotic bone lesions, capillary malformation, bilateral nephrogenic rests and Wilms tumors, and a novel complex renal vascular anomaly that resembles Fibro-Adipose Vascular Anomaly (FAVA). This report further expands the phenotypic spectrum of somatic RASopathies, and discusses the potential phenotypic and pathogenetic overlap with -related overgrowth disorders, specifically CLOVES. The occurrence of a secondary cancer hotspot mutation ( p.R479G in the Wilms tumor, but not the associated nephrogenic rest, moreover suggests that additional driver mutations are involved in the development of Wilms tumor in somatic overgrowth disorders.
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http://dx.doi.org/10.1177/1093526620986502DOI Listing
February 2021

De novo missense variants in are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

J Med Genet 2020 Aug 20. Epub 2020 Aug 20.

Maternal and Child Health Hospital of Hunan Province, Changsha, China.

Objective: To determine the potential disease association between variants in and complex multisystem neurological and developmental delay phenotypes.

Methods: Here we describe a series of de novo missense variants in in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.

Results: encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.

Conclusion: These findings indicate that rare de novo variants in can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring variants may lead to a better understanding of the function of this ubiquitously expressed gene.
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http://dx.doi.org/10.1136/jmedgenet-2020-107137DOI Listing
August 2020

Universal Testing to Identify Lynch Syndrome Among Women With Newly Diagnosed Endometrial Carcinoma.

J Obstet Gynaecol Can 2020 Feb 1;42(2):137-143. Epub 2019 Nov 1.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB; Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB.

Background: Lynch syndrome (LS) is an autosomal dominant cancer syndrome caused by a germline mutation in the mismatch repair (MMR) genes. Protocols based on immunohistochemical expression of MMR proteins in cancer are used to identify patients with LS.

Methods: The universal LS screening protocol of the Tom Baker Cancer Centre (Calgary, AB) of all patients diagnosed between April 1, 2013 and April 1, 2015 with endometrioid carcinoma of the endometrium was audited through a retrospective chart review. LS status and frequency of protocol compliance at each of the key steps were calculated (Canadian Task Force Classification II-2).

Results: The cohort consisted of 375 patients. MMR immunohistochemical testing was requested for 321 (85.6%). Expression of at least one protein was lost in 86 (26.8%). Twenty-one (6.5%) patients were eligible for genetic counselling because PMS2, MSH2, or MSH6 protein expression was lost in 19, and two patients had a family history of LS. Eleven (91.7%) of 12 (57.1%) who attended had germline testing, and six (54.5%) showed a mutation diagnostic of LS. LS status among the cohort of 375 patients was positive in six (1.6%), negative in 294 (78.4%), and unknown in 75 (20%) because of protocol non-compliance. LS was confirmed in six (2%) of the 321 women who completed the protocol.

Conclusion: This is the first audit of a Canadian-based universal LS screening protocol of patients with endometrial cancer. The success of the protocol is endorsed by the 80% compliance and by the 2% prevalence of LS, which is within the published range.
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http://dx.doi.org/10.1016/j.jogc.2019.06.018DOI Listing
February 2020

Correction: A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

Genet Med 2019 Sep;21(9):2159-2160

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.

The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0413-xDOI Listing
September 2019

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

Genet Med 2019 05 24;21(5):1058-1064. Epub 2018 Sep 24.

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.

Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes.

Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed.

Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants.

Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.
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http://dx.doi.org/10.1038/s41436-018-0290-3DOI Listing
May 2019

Evolution of genetic assessment for BRCA-associated gynaecologic malignancies: a Canadian multisociety roadmap.

J Med Genet 2018 09 24;55(9):571-577. Epub 2018 Jul 24.

Familial Breast & Ovarian Cancer Clinic, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of -related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for -associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.
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http://dx.doi.org/10.1136/jmedgenet-2018-105472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119348PMC
September 2018

Mosaic trisomy 1q: a recurring chromosome anomaly that is a diagnostic challenge and is associated with a Fryns-like phenotype.

Prenat Diagn 2017 Jun 23;37(6):602-610. Epub 2017 May 23.

Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Calgary, Canada.

Objective: Trisomy of the long arm of chromosome 1 is a very rare cytogenetic anomaly that is difficult to diagnose because of tissue-limited mosaicism. This study aimed to further characterize the prenatal and post-natal findings associated with this anomaly, including the first reported chromosomal microarray finding.

Method: This is a retrospective study of six cases of mos 46,X,der(Y)t(Y;1)(q12;q21)/46,XY, diagnosed both prenatally and post-natally. Detailed clinical features and pregnancy outcome were documented.

Results: Recurrent prenatal and post-natal features of our case series, as well as the previously reported cases, were described, suggesting a Fryns-like phenotype. A diagnosis of mosaic trisomy 1q is difficult to confirm post-natally in some cases because of the tissue provided for analysis, emphasizing the need to study multiple tissue types in cases of fetal loss with a suspected underlying chromosomal imbalance.

Conclusion: The overlap of clinical features between mosaic trisomy 1q and Fryns syndrome emphasizes the need to obtain appropriate samples for genetic analysis. The present cases and a review of the literature suggest that partial trisomy of the long arm of chromosome 1 is a distinct de novo clinical entity with low recurrence risk. © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.5058DOI Listing
June 2017

Metachronous Type I pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child.

Pediatr Blood Cancer 2016 12 21;63(12):2240-2242. Epub 2016 Jul 21.

Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Pleuropulmonary blastoma (PPB) is a rare childhood tumor, often associated with germline DICER1 mutations and a risk for development of other benign and malignant tumors, a constellation termed DICER1 syndrome. A 1-year-old male was diagnosed with Type I PPB and screened regularly thereafter for detection of intrathoracic and intraabdominal disease. Ten months after diagnosis of PPB, he presented with headaches and vomiting. He was diagnosed with atypical choroid plexus papilloma, a lesion not previously reported with PPB. The presence of central nervous system symptoms in patients with PPB or a phenotype suggestive of DICER1 syndrome should prompt early intracranial imaging.
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http://dx.doi.org/10.1002/pbc.26160DOI Listing
December 2016

Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma.

Cancer Genet 2016 Jul-Aug;209(7-8):359-63. Epub 2016 Jun 3.

Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, allele-specific (AS)-PCR for a somatic nonsense mutation confirmed that a temple mass was metastatic retinoblastoma. In a second patient, a rib mass shared somatic copy number gains and losses with the primary tumor. For definitive diagnosis, however, an RB1 mutation was needed, but heterozygous promoter→exon 11 deletion was the only RB1 mutation detected in the primary tumor. We used a novel application of inverse PCR to identify the deletion breakpoint. Subsequently, AS-PCR designed for the breakpoint confirmed that the rib mass was metastatic retinoblastoma. These cases demonstrate that personalized molecular testing can confirm retinoblastoma metastases and rule out a second primary cancer, thereby helping to direct the clinical management.
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http://dx.doi.org/10.1016/j.cancergen.2016.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970893PMC
May 2017

Birt-Hogg-Dubé syndrome: a large single family cohort.

Respir Res 2016 Feb 29;17:22. Epub 2016 Feb 29.

Department of Medicine, University of Calgary, Calgary, AB, Canada.

Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function.

Methods: The study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen.

Results: Thirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35-7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41-29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results.

Conclusions: This is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden.
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http://dx.doi.org/10.1186/s12931-016-0339-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770529PMC
February 2016

Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.

Histopathology 2016 Aug 26;69(2):288-97. Epub 2016 Feb 26.

Department of Pathology and Laboratory Medicine, Calgary Laboratory Services/Alberta Health Services and University of Calgary, Calgary, AB, Canada.

Aims: Lynch syndrome screening in ovarian carcinoma is controversial. The aim of this study was to assess the frequency of deficient mismatch repair (dMMR) protein in a retrospective cohort enriched for non-high-grade serous carcinomas and its association with outcome within histological types.

Methods And Results: Tissue microarrays representing 612 ovarian carcinomas were tested for mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry. dMMR was detected in 13.8% of endometrioid and 2.4% of clear cell carcinomas, but not in other histological types. Within endometrioid carcinomas, 11 of 25 dMMR cases showed abnormal MLH1/PMS2, 10 cases showed abnormal MSH2/MSH6, and four cases showed only abnormal MSH6, indicating that at least 7.7% of endometrioid carcinomas have dMMR probably related to Lynch syndrome. The four dMMR clear cell carcinomas showed abnormal MSH2/MSH6 in three cases and only abnormal MSH6 in one case, all probably related to Lynch syndrome. Within endometrioid carcinomas, dMMR was significantly associated with age <50 years, synchronous endometrial endometrioid carcinoma, a higher CA125 level at diagnosis, higher FIGO grade, absence of ARID1A, and at least 20 CD8-positive intraepithelial lymphocytes per high-power field, but was not associated with cancer-specific death. Age <50 years, higher CA125 levels at diagnosis and at least 20 CD8-positive intraepithelial lymphocytes per high-power field remained significant after adjustment for multiple testing, but their sensitivity for identifying dMMR remained insufficient.

Conclusion: Our data support the policy of histotype-specific Lynch syndrome screening in ovarian carcinoma confined to endometrioid and clear cell carcinomas.
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http://dx.doi.org/10.1111/his.12934DOI Listing
August 2016

Bilateral congenital lumbar hernias in a patient with central core disease--A case report.

Neuromuscul Disord 2016 Jan 5;26(1):56-9. Epub 2015 Nov 5.

Department of Medical Genetics, Alberta Children's Hospital, Calgary, Alberta, Canada; Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.

Congenital lumbar hernias are rare malformations caused by defects in the development of the posterior abdominal wall. A known association exists with lumbocostovertebral syndrome; however other associated anomalies, including one case with arthrogryposis, have been previously reported. We present an infant girl with bilateral congenital lumbar hernias, multiple joint contractures, decreased muscle bulk and symptoms of malignant hyperthermia. Molecular testing revealed an R4861C mutation in the ryanodine receptor 1 (RYR1) gene, known to be associated with central core disease. This is the first reported case of the co-occurrence of congenital lumbar hernias and central core disease. We hypothesize that ryanodine receptor 1 mutations may interrupt muscle differentiation and development. Further, this case suggests an expansion of the ryanodine receptor 1-related myopathy phenotype to include congenital lumbar hernias.
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http://dx.doi.org/10.1016/j.nmd.2015.10.011DOI Listing
January 2016

Focal dermal hypoplasia: report of a case with myelomeningocele, Arnold-Chiari malformation and hydrocephalus with a review of neurologic manifestations of Goltz syndrome.

Pediatr Dermatol 2014 Mar-Apr;31(2):220-4. Epub 2014 Jan 5.

Division of Dermatology, University of Calgary, Calgary, Alberta, Canada.

Focal dermal hypoplasia (Goltz syndrome, Online Mendelian Inheritance in Man [OMIM] 305600) is a rare X-linked dominant congenital disorder involving defects of mesodermal- and ectodermal-derived structures. It is associated with mutations in the PORCN gene, a regulator of Wnt signaling proteins. The phenotype is highly variable, although all describe characteristic skin findings as a primary diagnostic feature. To date there are few case reports of focal dermal hypoplasia associated with central nervous system abnormalities. We report the second case of focal dermal hypoplasia associated with myelomenigocele, Arnold-Chiari malformation and hydrocephalus and the first in a male. Genetic testing identified a novel mosaic three base pair deletion within the PORCN gene (c.853_855delACG). This case highlights the importance of neurological evaluation in focal dermal hypoplasia and consideration of other syndromes more commonly associated with central nervous system abnormalities. In this report we summarize the literature on neurological manifestations in Goltz syndrome.
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http://dx.doi.org/10.1111/pde.12267DOI Listing
January 2015

Cancer risks for relatives of patients with serrated polyposis.

Am J Gastroenterol 2012 May 24;107(5):770-8. Epub 2012 Apr 24.

Centre for MEGA Epidemiology, School of Population Health, University of Melbourne, Carlton, Victoria, Australia.

Objectives: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis.

Methods: A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population.

Results: A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate.

Conclusions: Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.
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http://dx.doi.org/10.1038/ajg.2012.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488375PMC
May 2012

Risk factors for colorectal cancer in patients with multiple serrated polyps: a cross-sectional case series from genetics clinics.

PLoS One 2010 Jul 16;5(7):e11636. Epub 2010 Jul 16.

Familial Cancer Laboratory, QIMR, Herston, Queensland, Australia.

Background: Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.

Methods And Findings: We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.

Conclusion: A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011636PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905435PMC
July 2010