Kristin B. Niendorf

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of familys mutations) and the Netherlands (c.225_243del19, 90% of familys mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Correlation of Polyp Number and Family History of Colon Cancer With Germline MYH Mutations

BACKGROUND & AIMS Affected individuals with biallelic MYH mutations are believed to display multiple adenomatous polyps without evidence of vertical transmission. Our goal was to determine the detection rate of germline MYH mutations in a high-risk gastrointestinal cancer clinic population by using polyp number as a selection criterion. METHODS Patients were screened for the 2 most common MYH mutations: Y165C and G382D. The complete MYH coding region was sequenced in cases with a heterozygous mutation. RESULTS Among 45 patients with more than 15 adenomatous polyps not diagnosed with familial adenomatous polyposis, 7 (15.6%) had biallelic MYH mutations. When 122 participants from a high-risk gastrointestinal cancer clinic who did not fulfill these criteria were tested, 2 additional patients with biallelic mutations were identified. Both had young-onset colorectal cancer (age, <50 y) with fewer than 15 polyps. Surprisingly, most of the 9 patients with biallelic MYH mutations reported family histories consistent with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), with 7 cases meeting at least 1 of the Bethesda criteria, 5 cases fulfilling 3 Bethesda criteria, and 2 cases fulfilling the Amsterdam II criteria. CONCLUSIONS Most individuals with MYH mutations exhibit multiple adenomatous polyps. However, 22% of cases were missed when this was the sole criterion for germline testing. A significant number reported a strong family history of cancer that was consistent with HNPCC. MYH testing thus can be considered for patients who meet clinical criteria for HNPCC in the absence of DNA mismatch repair gene mutations.

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

The CHEK2‐1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early‐onset disease; functionally characterized new variants and conducted a population‐based case–control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2‐H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2‐1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early‐onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2‐positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2‐P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low‐penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically‐ and geographically‐selected populations.

What’s the Harm? Genetic Counselor Perceptions of Adverse Effects of Genetics Service Provision by Non-Genetics Professionals

Anecdotal accounts suggest some patients have experienced negative outcomes as a result of receiving genetics services from non-genetics providers, but empirical evidence of these incidents and their outcomes is limited. This study examined genetic counselors’ perceptions of the occurrence of such incidents in the state of Minnesota. Twenty-five genetic counselors completed an on-line survey and 20 also participated in a semi-structured telephone interview. The interviewees recalled and described 37 specific incidents they perceived as having negative outcomes for patients and/or their families. Inductive and cross-case analysis revealed common themes including: adverse psychosocial effects, inadequate genetic counseling, genetic testing and screening errors, medical mismanagement, negative shifts in attitudes toward medical providers, and unnecessary use of health care resources. Commonly mentioned strategies for preventing/mitigating negative outcomes included: educational outreach and awareness programs for medical providers and the general public, standardized testing and screening processes, and implementing mechanisms for reporting and addressing adverse events. Additional findings, practice and policy implications, and research recommendations are discussed.

MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability

Background: Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier. Methods: We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation. Results: From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic regression model (MELPREDICT) is given by where L = 1.99+[0.92×(no. of proband primaries)]+[0.74×(no. of additional family primaries)]−[2.11×ln(age)]. The mean estimated probabilities for subjects in the Boston dataset were 55.4% and 5.1% for the mutation carriers and non-carriers respectively. In a receiver operator characteristic analysis, the area under the curve was 0.881 (95% confidence interval 0.739 to 1.000) for the Boston model set (n = 116) and 0.803 (0.729 to 0.877) for an external Toronto hereditary melanoma cohort (n = 143). Conclusions: These results represent the first-iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance.

Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO

Personalized cancer risk assessment remains an essential imperative in postgenomic cancer medicine. In hereditary melanoma, germline CDKN2A mutations have been reproducibly identified in melanoma-prone kindreds worldwide. However, genetic risk counseling for hereditary melanoma remains clinically challenging. To address this challenge, we developed and validated MelaPRO, an algorithm that provides germline CDKN2A mutation probabilities and melanoma risk to individuals from melanoma-prone families. MelaPRO builds on comprehensive genetic information, and uses Mendelian modeling to provide fine resolution and high accuracy. In an independent validation of 195 individuals from 167 families, MelaPRO exhibited good discrimination with a concordance index (C) of 0.86 [95% confidence intervals (95% CI), 0.75-0.97] and good calibration, with no significant difference between observed and predicted carriers (26; 95% CI, 20-35, as compared with 22 observed). In cross-validation, MelaPRO outperformed the existing predictive model MELPREDICT (C, 0.82; 95% CI, 0.61-0.93), with a difference of 0.05 (95% CI, 0.007-0.17). MelaPRO is a clinically accessible tool that can effectively provide personalized risk counseling for all members of hereditary melanoma families.

Cutaneous melanoma: Family screening and genetic testing

ABSTRACT:  The incidence of cutaneous melanoma (CM) has been steadily increasing in recent decades. Ultraviolet radiation (UVR) exposure, in the form of intermittent heavy exposure and severe sunburns in childhood, is believed to be the most important environmental contribution to CM risk. Genetic determinants also modulate CM risk, probably to a greater extent than environmental exposure. Certain heritable traits such as prominent numbers of common and atypical melanocytic nevi, skin type, dense UVR‐induced freckling, and hair color are all known to be associated with increased CM risk. Very rarely, a heritable mutation in a high‐risk gene renders the susceptible individual at extreme risk for CM. Families may carry one or more of the other high‐risk phenotypic traits leading to uncertainty about how to quantify CM risk and provide management recommendations. Commercial genetic testing for the known high‐risk inherited genetic mutations is available but is only relevant for those rare families likely to be carrying identifiable mutations. CM screening and risk intervention programs are being established internationally for families at markedly increased risk. Algorithms based on the level of risk are proposed.

Genetic Counseling for Cancer: Technology Promises Better Screening for Hereditary Cancer Patients

Approximately 100,000 cases of cancer in the U.S. each year are due to inherited genetic conditions. Scores of hereditary cancer syndromes have been described, associated with nearly every cancer type, and prevention measures have proven to decrease cancer risk. With the advent of new technology, increasingly complex genetic testing options exist. Specially trained genetic counselors coordinate the identification, testing, education and care of patients with hereditary cancer risks. Thus, genetic counselors are at the forefront of the integration of new technology into medical care for hereditary cancer patients. New methods test many more genes, faster and more affordably but with the potential challenges of uninformative or undesired information. Additionally, algorithms using these tests will revolutionize the screening of large numbers of people for hereditary cancer syndromes. Genetic counselors are prepared to offer a broad range of testing schemas as well as provide education regarding the impact of the results for providers, patients and families.

A qualitative study of barriers to genetic counseling and potential for mobile technology education among women with ovarian cancer

BackgroundNational guidelines recommend genetic counseling for all ovarian cancer patients because up to 20% of ovarian cancers are thought to be due to hereditary cancer syndromes and effective cancer screening and prevention options exist for at-risk family members. Despite these recommendations, uptake of genetic counselling and testing is low. The goal of this study was to identify barriers to and motivators for receipt of genetic counseling along with preferences regarding potential use of a mobile application to promote genetic counseling.MethodsThree focus groups were conducted including 14 women with a diagnosis of epithelial ovarian, primary peritoneal or fallopian tube cancer. Topics included understanding of genetic counseling, perceived pros and cons, preferences for receiving health information, and familiarity with mobile phone technology. Transcripts were analyzed using standard procedures of qualitative thematic text analysis and descriptive coding techniques.ResultsSix major themes regarding barriers to and motivators of genetic counseling and use of mobile technology in promoting genetic counseling emerged: (1) need for information, (2) relevance, (3) emotional concerns, (4) family concerns, (5) practical concerns, and (6) mobile application considerations.ConclusionsThese data reiterate previously reported barriers to genetic counseling as observed in other populations. Participants were supportive of the use of mobile technology for promoting uptake of genetic counseling.

Results of a pilot study to improve identification and referral for people at high risk for hereditary colorectal cancer syndromes

Background Five percent of colorectal cancers are attributable to hereditary syndromes for which genetic testing is clinically available. Effective surveillance strategies and riskreducing surgeries lower risk for people diagnosed with inherited colorectal cancer syndromes. However, from a public health standpoint, the existence of effective interventions is futile if not applied broadly and appropriately to the population at risk. Efficient identification of people with hereditary risk remains a challenge, and failure to systematically identify people at high hereditary risk results in preventable morbidity and mortality. The William C. Bernstein M.D. Familial Cancer Registry (Bernstein Registry) is a research-based program that triages participants for hereditary cancer risk. Selfreported family histories are assessed and participants are given tailored information about their hereditary risk factors. People at high risk are given information about the availability and advisability of clinical genetics services. Pilot populations are being enrolled to establish registry processes and determine the feasibility of implementation at a population-based level. This pilot group includes volunteers from a previously established colorectal cancer registry. Materials and methods A 7-item screening questionnaire determines potential eligibility for the Bernstein Registry using elements of early onset, multiple primary and family history of cancers. Potentially eligible participants are contacted by telephone and a four-generation cancer history is generated via guided interview. Pedigrees are analyzed by genetic counselors for hereditary cancer risk probabilities based on published guidelines. Targeted, tailored risk information is provided in writing along with a copy of the family tree. A list of genetic counseling service providers is included for people at high risk.