Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor. (C) 2014 Elsevier Inc. All rights reserved

Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models.

Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference ≤ 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum.This work was primarily supported by grant 1129136 from the Australian National Health and Medical Research Council (NHMRC) (https://www.nhmrc.gov.au/). MCCS cohort recruitment was funded by Cancer Council Victoria (https://www.cancervic.org.au/) and VicHealth (https://www.vichealth.vic.gov.au/). The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383, and ongoing follow-up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.TN-D is a recipient of a Career Development Fellowship from the National Breast Cancer Foundation (Australia). JLH and MCS are Senior Principal and Senior Research Fellows of the National Health and Medical Research Council (Australia), respectively. ACA and AJL are supported by grants from Cancer Research UK (C12292/A20861 and PPRPGM19 Nov20\100002)

The National Dutch Breast Implant Registry: user-reported experiences and importance

Background: Robust (inter-)national breast implant registries are important. For some, registries are an administrative burden, for others they represent a solution for the discussions involving breast implants. The DBIR is one of the first national, opt-out, clinical registries of breast implants, providing information for clinical auditing and product recall. Four years after its introduction, it is time to address users’ comments in order to keep improving quality of registration, and patient safety. This study assesses users’ feedback focusing on importance of registration, logistics and user experience, and areas of improvement. Methods: In May 2018, a standardized online study–specific questionnaire was sent out to all members of the Netherlands Society of Plastic Surgery. Descriptive statistics were reported in absolute frequencies and/or percentages. Results: A total of 102 members responded to the questionnaire (response rate, 24.2%). Of all respondents, 97.1% were actively registering in DBIR. Respondents rated the importance of registration in DBIR as 8.1 out of 10 points. Ninety-one respondents suggested improvements for the DBIR. All comments were related to registration convenience and provision of automatically generated data. Conclusions: Respondents believe that registration is highly important and worth the administrative burden. However, we should collectively keep improving accuracy, usability and sustainability of breast

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al

A PALB2 mutation associated with high risk of breast cancer

Introduction: As a group, women who carry germline mutations in partner and localizer of breast cancer 2 susceptibility protein (PALB2) are at increased risk of breast cancer. Little is known about by how much or whether risk differs by mutation or family history, owing to the paucity of studies of cases unselected for family history.Methods: We screened 1,403 case probands for PALB2 mutations in a population-based study of Australian women with invasive breast cancer stratified by age at onset. The age-specific risk of breast cancer was estimated from the cancer histories of first- and second-degree relatives of mutation-carrying probands using a modified segregation analysis that included a polygenic modifier and was conditioned on the carrier case proband. Further screening for PALB2 c.3113G > A (W1038X) was conducted for 779 families with multiple cases of breast cancer ascertained through family cancer clinics in Australia and New Zealand and 764 population-based controls.Results: We found five independent case probands in the population-based sample with the protein-truncating mutation PALB2 c.3113G > A (W1038X); 2 of 695 were diagnosed before age 40 years and 3 of 708 were diagnosed when between ages 40 and 59 years. Both of the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families. No c.3113G > A (W1038X) carriers were found in 764 population-based unaffected controls. The hazard ratio was estimated to be 30.1 (95% confidence interval (CI), 7.5 to 120; P A mutation appears to be associated with substantial risks of breast cancer that are of clinical relevance. © 2010 Southey et al.; licensee BioMed Central Ltd

Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer

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