Medicine (RMH) - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 29
-
ItemGenomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome(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.
-
ItemTumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome(WILEY, 2019-07)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.
-
ItemType 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome(NATURE PUBLISHING GROUP, 2019-11-12)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 included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.
-
ItemNo Preview AvailableCancer Risks for PMS2-Associated Lynch Syndrome(AMER SOC CLINICAL ONCOLOGY, 2018-10-10)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.
-
ItemNo Preview AvailableAbility of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history(SPRINGER, 2019-10)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 with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.
-
ItemCancer Risks for PMS2-Associated Lynch Syndrome (vol 29, pg 2961, 2018)(AMER SOC CLINICAL ONCOLOGY, 2019-03-20)This corrects the article "Cancer Risks for PMS2-Associated Lynch Syndrome" in volume 36 on page 2961.
-
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.
-
ItemSomatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas(SPRINGER, 2018-01)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 B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.
-
ItemRisk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1(NATURE PUBLISHING GROUP, 2018-08)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 diagnosed in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis. RESULTS: We observed 67 CRCs (mean age at diagnosis = 50.2 (SD = 13.8) years) among 364 first- and second-degree relatives from 41 POLE families, and 6 CRCs (mean age at diagnosis = 39.7 (SD = 6.83) years) among 69 relatives from 9 POLD1 families. We estimated risks of CRC up to the age of 70 years (95% confidence interval) for males and females, respectively, to be 28% (95% CI, 10–42%) and 21% (95% CI, 7–33%) for POLE mutation carriers and 90% (95% CI, 33–99%) and 82% (95% CI, 26–99%) for POLD1 mutation carriers. CONCLUSION: CRC risks for POLE mutation carriers are sufficiently high to warrant consideration of colonoscopy screening and implementation of management guidelines recommended for MSH6 mutation carriers in cases of Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.
-
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.