Mark Clendenning

• Ph.D.
• Laboratory Manager at University of Melbourne

Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DNA MMR genes MLH1 , MSH2 , MSH6 and PMS2 , but other causes include somatic MLH1 gene promoter hypermethylation, constitutional MLH...

Background The adverse gut microbiome may underlie the variability in risks of colorectal cancer (CRC) and metachronous CRC in people with Lynch syndrome (LS). The role of pks+/−Escherichia coli (pks+/−E. coli), Enterotoxigenic Bacteroides fragilis (ETBF), and Fusobacterium nucleatum (Fn) in CRCs and adenomas in people with LS is unknown. Methods...

Background Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these m...

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these...

Introduction/Background In PHAEDRA, a single arm Phase 2 trial (n=71), MMR deficiency (dMMR) was predictive of response to durvalumab (1500mg IV Q4W), with an objective tumour response rate (OTR; defined by iRECIST) of 47% in dMMR compared with 3% in MMR-proficient (pMMR) women with advanced endometrial cancer (AEC). We investigated tumour genomic...

Background This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks + Escherichia coli ( pks + E.coli + ), pks + E.coli - (non- E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum ( F. nucleatum ). Methods We screened 1697 tumo...

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1 , a gene associated with breast and ovarian cancer and RNF43 , a gene associated wi...

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight...

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight...

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch synd...

Background MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylat...

5604 Background: In the single arm phase 2 PHAEDRA trial, MMR deficiency (dMMR) was predictive of response to durvalumab (1500mg IV Q4W), with an objective tumor response rate (OTR; defined by iRECIST) of 47% in dMMR compared with 3% in MMR-proficient (pMMR) advanced endometrial cancer (AEC). This substudy of the PHAEDRA trial investigates MMR mole...

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted...

Germline pathogenic variants in the DNA mismatch (MMR) repair genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6 :c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syn...

Background and Aims The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated...

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted p...

Objective The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)²⁰¹⁰ clinical criteria and by colorectal cancer (CRC). Method A retrospective case-control study involving a cross-sectional analysis from 350 un...

Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. Tumor features, individually and in combination, derived from whole-exome sequenced (WES) colorectal cancers (CRCs) and panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) were assessed for their accuracy in detecting dMMR. CRCs...

Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. We assessed tumor features, individually and in combination, in whole-exome sequenced (WES) colorectal cancers (CRCs) and in panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) for their accuracy in detecting dMMR. CRCs (n=300)...

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and...

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyp...

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Ge...

Objective A genomic test to predict personal risk of colorectal cancer (CRC) that targets screening and could be feasibly implemented in primary care. We explored informed decision-making and attitudes towards genomic testing in this setting. Methods A CRC genomic test was offered to 150 general practice patients with brief discussion of its impli...

Background Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer be...

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (I...

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to pre...

Background The role of DNA methylation (DNAm) in the carcinogenesis of colorectal cancer (CRC) diagnosed <50years of age (early-onset CRC or EOCRC) is currently unknown. We investigated aberrant DNAm changes and the contribution of ageing-associated methylomic drift, and age acceleration to EOCRC carcinogenesis. Methods Genome-wide DNAm profiling...

It was not known whether the polygenic risk scores (PRS) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established SNPs associated with colorectal cancer in European populations for 826 European-desc...

Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH 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. Design Whole-exome...

Objective Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH 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. Design Whole exome...

People who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing was applied to identify the underlying...

Introduction: Genomic tests can predict risk and tailor screening recommendations for colorectal cancer (CRC). Primary care could be suitable for their widespread implementation. Objective: We aimed to assess the feasibility and acceptability of administering a CRC genomic test in primary care. Methods: Participants aged 45-74 years recruited...

Background: Colorectal cancer (CRC) comprises different molecular subtypes, including those tumors that develop defective DNA mismatch repair (MMR) evidenced by microsatellite instability (MSI) and/or loss of MMR protein expression (MMR-deficiency). Tumor MMR-deficiency can result from inherited causes, namely germline mutations in the MMR genes (L...

Background People who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of the MLH1 gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches...

The advent of gene panel testing is challenging the previous practice of using clinically defined cancer family syndromes to inform single-gene genetic screening. Individual and family cancer histories that would have previously indicated testing of a single gene or a small number of related genes are now, increasingly, leading to screening across...

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation...

Background: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. Methods: This study...

Background Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation. Methods Whole exom...

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected h...

Purpose: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. Patients and methods: We performed targeted sequencing of 17 UTUCs from patients with documente...

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 defin...

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new geno...

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new geno...

Background A number of single nucleotide polymorphisms (SNPs), which are common inherited genetic variants, have been identified that are associated with risk of colorectal cancer. The aim of this study was to determine the ability of these SNPs to estimate colorectal cancer (CRC) risk for persons with and without a family history of CRC, and the s...

This corrects the article DOI: 10.1038/gim.2017.185.

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2...

Background: Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC). Methods: We identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases di...

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measureme...

Table S1. Individual Tier 1 variants. Table S2. Individual Tier 2 variants. Table S3. Individual in‐frame indels. Table S4. Alternative splicing variants.

Figure S1. Missense variant classification.

Characterisation of mismatch repair variants submitted to the international mismatch repair consortium (IMRC)

Background Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next‐generation sequencing technologies have made it possibl...

The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for s...

The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite u...

Background: Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical (IHC) loss of MMR protein expression, is used diagnostically to identify individuals with Lynch syndrome. A high proportion of colorectal cancers (CRCs) and endometrial cancers (ECs) that demonstrate tumor MMR-deficiency are categorised as having “Lynch-like synd...

Background: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC) and an evolving management approach. The aims of this study were to assess the polyp burden reduction over time, and the incidence of CRC in serrated polyposis patients undergoing community surveillance. Methods: This is an observational...

Background TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathologica...

Introduction: Population- and family-based studies suggest germline predisposition in up to 35% of colorectal cancer (CRC) cases. Known genetic factors, including three highly penetrant Mendelian cancer syndromes and approximately 45 low penetrant alleles, account for less than 15% of all CRC and only a small proportion of early onset CRC. Identify...

BACKGROUND: While high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. METHODS: We studied the families of 5,744 colorectal cancer cases (probands)...

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal canc...

DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The ro...

Dataset. (CSV)

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal canc...

Background: 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. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family...

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (proband...

MicroRNAs (miRNAs) regulate up to one-third of all protein-coding genes including genes relevant to cancer. Variants within miRNAs have been reported to be associated with prognosis, survival, response to chemotherapy across cancer types, in vitro parameters of cell growth, and altered risks for development of cancer. Five miRNA variants have been...

Supporting Information

Serrated polyposis syndrome (SPS) is characterised by the occurrence of multiple serrated polyps in the large bowel. Defined clinically by the 2010 revised WHO, SPS is associated with an increased risk of colorectal cancer (CRC) for affected individuals and their first-degree relatives. Yan et al 1 recently reported their findings from whole-exome...

Purpose: Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter-enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer (CRC)...

Background and aim: Tumour testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilising a combination of tumour and germline test...

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Fam...

Background: People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers. Methods: This study included 1966 (56% female) carriers of an MMR gen...

Aim: To determine whether single nucleotide polymorphisms (SNPs) can be used to identify people who should be screened for colorectal cancer. Methods: We simulated one million people with and without colorectal cancer based on published SNP allele frequencies and strengths of colorectal cancer association. We estimated 5-year risks of colorectal...

Objectives: Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline...

Lynch syndrome is an inherited cancer-predisposing disorder caused by germline mutations in the DNA mismatch repair (MMR) genes but there is a high degree of variability in cancer risk observed among carriers, suggesting the existence of modifying factors. Our aim was to investigate variants within the hTERT gene as a potential colorectal cancer (C...

Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this...