Medicine (RMH) - Research Publications

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    Germline MBD4 deficiency causes a multi-tumor predisposition syndrome
    Palles, C ; West, HD ; Chew, E ; Galavotti, S ; Flensburg, C ; Grolleman, JE ; Jansen, EAM ; Curley, H ; Chegwidden, L ; Arbe-Barnes, EH ; Lander, N ; Truscott, R ; Pagan, J ; Bajel, A ; Sherwood, K ; Martin, L ; Thomas, H ; Georgiou, D ; Fostira, F ; Goldberg, Y ; Adams, DJ ; van der Biezen, SAM ; Christie, M ; Clendenning, M ; Thomas, LE ; Deltas, C ; Dimovski, AJ ; Dymerska, D ; Lubinski, J ; Mahmood, K ; van der Post, RS ; Sanders, M ; Weitz, J ; Taylor, JC ; Turnbull, C ; Vreede, L ; van Wezel, T ; Whalley, C ; Arnedo-Pac, C ; Caravagna, G ; Cross, W ; Chubb, D ; Frangou, A ; Gruber, AJ ; Kinnersley, B ; Noyvert, B ; Church, D ; Graham, T ; Houlston, R ; Lopez-Bigas, N ; Sottoriva, A ; Wedge, D ; Jenkins, MA ; Kuiper, RP ; Roberts, AW ; Cheadle, JP ; Ligtenberg, MJL ; Hoogerbrugge, N ; Koelzer, VH ; Rivas, AD ; Winship, IM ; Ponte, CR ; Buchanan, DD ; Power, DG ; Green, A ; Tomlinson, IPM ; Sampson, JR ; Majewski, IJ ; de Voer, RM (CELL PRESS, 2022-05-05)
    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 polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
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    "Left in limbo": Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis
    den Elzen, N ; Joseland, SL ; Saya, S ; Jonnagadla, S ; Isbister, J ; Winship, I ; Buchanan, DD (BMC, 2021-10-16)
    BACKGROUND: A diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis. METHODS: Semi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services. RESULTS: Participants' interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants' interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received. CONCLUSIONS: Our study findings highlight the variability in patients' interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.
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    Clinico-pathological predictors of mismatch repair deficiency in sebaceous neoplasia: A large case series from a single Australian private pathology service
    Walsh, MD ; Jayasekara, H ; Huang, A ; Winship, IM ; Buchanan, DD (WILEY, 2019-05-01)
    BACKGROUND/OBJECTIVES: Loss of expression of mismatch repair (MMR) proteins is frequently observed in sebaceous skin lesions and can be a herald for Lynch syndrome. The aim of this study was to identify clinico-pathological predictors of MMR deficiency in sebaceous neoplasia that could aid dermatologists and pathologists in determining which sebaceous lesions should undergo MMR immunohistochemistry (IHC). METHODS: An audit of sebaceous skin lesions (excluding hyperplasia) where pathologist-initiated MMR IHC was performed between January 2009 to December 2016 was undertaken from a single pathology practice identifying 928 lesions from 882 individuals. Lesions were further analysed for differences in gender, age at diagnosis, lesion type and anatomic location, stratified by MMR status. RESULTS: The 882 individuals (67.7% male) had a mean (SD) age of diagnosis of 68.4 ± 13.3 years. Nearly two-thirds of the lesions were sebaceous adenomas, with 82.6% of all lesions occurring on the head and neck. MMR deficiency, observed in 282 of the 919 lesions (30.7%), was most common in sebaceous adenomas (210/282; 74.5%). MMR-deficient lesions occurred predominantly on the trunk or limbs (64.7%), compared with 23.2% in head or neck (P < 0.001). Loss of MSH2 and MSH6 protein expression was most frequent pattern of loss (187/281; 66.5%). The highest AUC for discriminating MMR-deficient sebaceous lesions from MMR-proficient lesions was observed for the ROC curve based on subgroups defined by type and anatomic location of the sebaceous lesion (AUC = 0.68). CONCLUSION: The best combination of measured clinico-pathological features achieved only modest positive predictive values, sensitivity and specificity for identifying MMR-deficient sebaceous skin lesions.
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    Utility of immunohistochemistry for mismatch repair proteins on colorectal polyps in the familial cancer clinic
    Dow, E ; Buchanan, DD ; Winship, IM (WILEY, 2018-11-01)
    BACKGROUND: Immunohistochemistry for loss of expression of one or more of the mismatch repair proteins is performed on colorectal cancer tissue as a screening test for Lynch syndrome; however, its role in pre-malignant polyps remains controversial. AIM: To determine the effectiveness of mismatch repair immunohistochemistry performed on pre-malignant colorectal polyps in identifying Lynch syndrome, focusing on clinical utility and value. METHODS: A retrospective audit was conducted of mismatch repair immunohistochemistry performed on non-malignant polyps in patients who attended the Family Cancer Clinic at the Royal Melbourne Hospital. Two hundred and six patient records over a 10-year period (2006-2016) were reviewed. Personal and family history data were collected, including genetic testing results. RESULTS: Of the 57 patients who underwent polyp testing, the family histories comprised Amsterdam II Criteria (12.3%), Lynch syndrome-associated malignancies (42.1%), Lynch syndrome-associated malignancies and polyps (35.1%) and polyps only (8.8%); 10.5% of patients had no significant family history. Normal expression of the mismatch repair proteins was observed in 94.7% of patients; loss of expression was observed in three individuals with concordant germline variants in two patients (one PMS2 variant of unknown significance and one MSH6 mutation). Additional genetic testing in 21 patients with normal immunohistochemistry did not identify any additional Lynch syndrome cases. CONCLUSION: The clinical utility of mismatch repair immunohistochemistry on polyp tissue was low. No additional cases of Lynch syndrome were identified, and a large proportion of patients proceeded to germline testing despite normal polyp immunohistochemistry. We suggest there is no value in this approach.
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    No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
    Dominguez-Valentin, M ; Plazzer, J-P ; Sampson, JR ; Engel, C ; Aretz, S ; Jenkins, MA ; Sunde, L ; Bernstein, I ; Capella, G ; Balaguer, F ; Macrae, F ; Winship, IM ; Thomas, H ; Evans, DG ; Burn, J ; Greenblatt, M ; Cappel, WHDVTN ; Sijmons, RH ; Nielsen, M ; Bertario, L ; Bonanni, B ; Tibiletti, MG ; Cavestro, GM ; Lindblom, A ; Della Valle, A ; Lopez-Kostner, F ; Alvarez, K ; Gluck, N ; Katz, L ; Heinimann, K ; Vaccaro, CA ; Nakken, S ; Hovig, E ; Green, K ; Lalloo, F ; Hill, J ; Vasen, HFA ; Perne, C ; Buettner, R ; Goergens, H ; Holinski-Feder, E ; Morak, M ; Holzapfel, S ; Hueneburg, R ; Doeberitz, MVK ; Loeffler, M ; Rahner, N ; Weitz, J ; Steinke-Lange, V ; Schmiegel, W ; Vangala, D ; Crosbie, EJ ; Pineda, M ; Navarro, M ; Brunet, J ; Moreira, L ; Sanchez, A ; Serra-Burriel, M ; Mints, M ; Kariv, R ; Rosner, G ; Pinero, TA ; Pavicic, WH ; Kalfayan, P ; ten Broeke, SW ; Mecklin, J-P ; Pylvanainen, K ; Renkonen-Sinisalo, L ; Lepisto, A ; Peltomaki, P ; Hopper, JL ; Win, AK ; Buchanan, DD ; Lindor, NM ; Gallinger, S ; Le Marchand, L ; Newcomb, PA ; Figueiredo, JC ; Thibodeau, SN ; Therkildsen, C ; Hansen, TVO ; Lindberg, L ; Rodland, EA ; Neffa, F ; Esperon, P ; Tjandra, D ; Moslein, G ; Seppala, TT ; Moller, P (MDPI, 2021-07-01)
    BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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    DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer
    Joo, JE ; Clendenning, M ; Wong, EM ; Rosty, C ; Mahmood, K ; Georgeson, P ; Winship, IM ; Preston, SG ; Win, AK ; Dugue, P-A ; Jayasekara, H ; English, D ; Macrae, FA ; Hopper, JL ; Jenkins, MA ; Milne, RL ; Giles, GG ; Southey, MC ; Buchanan, DD (MDPI, 2021-06-01)
    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 (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10-16) and young people without CRC (p = 5.8 × 10-6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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    Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer
    Jenkins, MA ; Buchanan, DD ; Lai, J ; Makalic, E ; Dite, GS ; Win, AK ; Clendenning, M ; Winship, IM ; Hayes, RB ; Huyghe, JR ; Peters, U ; Gallinger, S ; Le Marchand, L ; Figueiredo, JC ; Pai, RK ; Newcomb, PA ; Church, JM ; Casey, G ; Hopper, JL (OXFORD UNIV PRESS, 2021-03-08)
    It was not known whether the polygenic risk scores (PRSs) 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 single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
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    Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals
    Lacaze, P ; Sebra, R ; Riaz, M ; Tiller, J ; Revote, J ; Phung, J ; Parker, EJ ; Orchard, SG ; Lockery, JE ; Wolfe, R ; Strahl, M ; Wang, YC ; Chen, R ; Sisco, D ; Arnold, T ; Thompson, BA ; Buchanan, DD ; Macrae, FA ; James, PA ; Abhayaratna, WP ; Lockett, TJ ; Gibbs, P ; Tonkin, AM ; Nelson, MR ; Reid, CM ; Woods, RL ; Murray, AM ; Winship, I ; McNeil, JJ ; Schadt, E (NATURE PUBLISHING GROUP, 2020-07-01)
    PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.
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    Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome
    Donahue, TE ; Bagrodia, A ; Audenet, F ; Donoghue, MTA ; Cha, EK ; Sfakianos, JP ; Sperling, D ; Al-Ahmadie, H ; Clendenning, M ; Rosty, C ; Buchanan, DD ; Jenkins, M ; Hopper, J ; Winship, I ; Templeton, AS ; Walsh, MF ; Stadler, ZK ; Iyer, G ; Taylor, B ; Coleman, J ; Lindor, NM ; Solit, DB ; Bochner, BH (AMER SOC CLINICAL ONCOLOGY, 2018-01-23)
    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 documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC. RESULTS: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC. CONCLUSION: LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.
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    Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome
    Georgeson, P ; Walsh, MD ; Clendenning, M ; Daneshvar, S ; Pope, BJ ; Mahmood, K ; Joo, JE ; Jayasekara, H ; Jenkins, MA ; Winship, IM ; Buchanan, DD (WILEY, 2019-07-01)
    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 exome sequencing was performed on three MMR-deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR-proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. RESULTS: Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR-deficient lesions from the MSH2 carriers compared with the MMR-proficient non-Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR-deficient lesions compared with the MMR-proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. CONCLUSION: Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch-related from non-Lynch sebaceous lesions.