Medicine (RMH) - Research Publications
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ItemFamily history-based colorectal cancer screening in Australia: A modelling study of the costs, benefits, and harms of different participation scenarios(PUBLIC LIBRARY SCIENCE, 2018-08)BACKGROUND: The Australian National Bowel Cancer Screening Programme (NBCSP) was introduced in 2006. When fully implemented, the programme will invite people aged 50 to 74 to complete an immunochemical faecal occult blood test (iFOBT) every 2 years. METHODS AND FINDINGS: To investigate colorectal cancer (CRC) screening occurring outside of the NBCSP, we classified participants (n = 2,480) in the Australasian Colorectal Cancer Family Registry (ACCFR) into 3 risk categories (average, moderately increased, and potentially high) based on CRC family history and assessed their screening practices according to national guidelines. We developed a microsimulation to compare hypothetical screening scenarios (70% and 100% uptake) to current participation levels (baseline) and evaluated clinical outcomes and cost for each risk category. The 2 main limitations of this study are as follows: first, the fact that our cost-effectiveness analysis was performed from a third-party payer perspective, which does not include indirect costs and results in overestimated cost-effectiveness ratios, and second, that our natural history model of CRC does not include polyp sojourn time, which determines the rate of cancerous transformation. Screening uptake was low across all family history risk categories (64%-56% reported no screening). For participants at average risk, 18% reported overscreening, while 37% of those in the highest risk categories screened according to guidelines. Higher screening levels would substantially reduce CRC mortality across all risk categories (95 to 305 fewer deaths per 100,000 persons in the 70% scenario versus baseline). For those at average risk, a fully implemented NBCSP represented the most cost-effective approach to prevent CRC deaths (AUS$13,000-16,000 per quality-adjusted life year [QALY]). For those at moderately increased risk, higher adherence to recommended screening was also highly cost-effective (AUS$19,000-24,000 per QALY). CONCLUSION: Investing in public health strategies to increase adherence to appropriate CRC screening will save lives and deliver high value for money.
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ItemAre the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?(ELSEVIER SCI LTD, 2013-05)BACKGROUND: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. METHODS: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). RESULTS: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52). CONCLUSIONS: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.
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ItemNo Preview AvailableTumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts(WILEY, 2017-02)BACKGROUND AND AIM: Tumor 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 utilizing a combination of tumor and germline testing approaches. METHODS: Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. RESULTS: Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. CONCLUSIONS: Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management.
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ItemNo Preview AvailableRisk factors for metachronous colorectal cancer following a primary colorectal cancer: A prospective cohort study(WILEY-BLACKWELL, 2016-09-01)
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ItemNo Preview AvailableScreening Practices of Unaffected People at Familial Risk of Colorectal Cancer(AMER ASSOC CANCER RESEARCH, 2012-02)Our objective was to determine screening practices of unaffected people in the general population at moderately increased and potentially high risk of colorectal cancer (CRC) because of their family history of the disease. A total of 1,627 participants in the Australasian Colorectal Cancer Family Registry study were classified into two CRC risk categories, according to the strength of their family history of the disease. We calculated the proportion of participants that adhered to national CRC screening guidelines by age group and for each familial risk category. We carried out a multinomial logistic regression analysis to evaluate the associations between screening and sociodemographic factors. Of the 1,236 participants at moderately increased risk of CRC, 70 (6%) reported having undergone guideline-defined "appropriate" screening, 251 (20%) reported some, but less than appropriate screening, and 915 (74%) reported never having had any CRC screening test. Of the 392 participants at potentially high risk of CRC, three (1%) reported appropriate screening, 140 (36%) reported some, but less than appropriate screening, and 249 (64%) reported never having had any CRC screening test. On average, those of middle age, higher education, and who had resided in Australia longer were more likely to have had screening for CRC. The uptake of recommended screening by unaffected people at the highest familial risk of developing CRC is extremely low. Guidelines for CRC screening are not being implemented in the population. More research is needed to identify the reasons so as to enable development of strategies to improve participation in screening.
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ItemNo Preview AvailableScreening practices of Australian men and women categorized as "at or slightly above average risk" of colorectal cancer(SPRINGER, 2012-11)PURPOSE: Australia has one of the highest incidences of colorectal cancer (CRC) in the world. In 2006, the federal government introduced a screening program consisting of a one-off fecal occult blood test offered to people turning 50, 55, or 65 years. We conducted a population-based study to estimate CRC screening practices existing outside the current program. METHODS: A total of 1887 unaffected subjects categorized "at or slightly above average risk" of CRC were selected from the Australasian Colorectal Cancer Family Registry. We calculated the proportions of participants that reported appropriate, under- and over-screening according to national guidelines. We performed a logistic regression analysis to evaluate associations between over-screening and a set of socio-demographic factors. RESULTS: Of 532 participants at average risk of CRC, eligible for screening, 4 (0.75 %) reported appropriate screening, 479 (90 %) reported never having been screened, 18 (3 %) reported some but less than appropriate screening, and 31 (6 %) reported over-screening. Of 412 participants aged 50 years or over, slightly above average risk of CRC, 1 participant (0.25 %) reported appropriate screening, 316 (77 %) reported no screening, and 11 (3 %) reported some but less than appropriate screening. Among participants under age 50 years, 2 % of those at average risk and 10 % of those slightly above average risk reported over-screening. Middle-aged people, those with a family history of CRC and those with a university degree, were more likely to be over-screened. CONCLUSION: Overall, the level of CRC screening participation was low and the vast majority of screening tests undertaken were inappropriate in terms of timing, modality, or frequency.
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ItemNo Preview AvailableRisk of Metachronous Colon Cancer Following Surgery for Rectal Cancer in Mismatch Repair Gene Mutation Carriers(SPRINGER, 2013-06)BACKGROUND: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer. METHODS: This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method. RESULTS: During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III. CONCLUSIONS: Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.
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ItemGermline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort(BMJ PUBLISHING GROUP, 2016-02)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 mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. DESIGN: This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). RESULTS: Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. CONCLUSIONS: A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.
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ItemRisk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer(W B SAUNDERS CO-ELSEVIER INC, 2014-05)We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.