Devki S. Saraiya

Identification of Cancer Patients with Lynch Syndrome: Clinically Significant Discordances and Problems in Tissue Based Mismatch Repair Testing

Tissue-based microsatellite instability (MSI) analysis and immunohistochemistry for DNA mismatch repair proteins are accepted screening tools to evaluate patients with cancer for Lynch syndrome. These laboratory analyses are thus important tools in cancer prevention. Quality assurance review was conducted to identify test discordances and problems. These results were then analyzed in conjunction with genetic testing outcomes. Six hundred and forty-six consecutive tumors from 2002 to 2010 were examined. MSI-low tumors were excluded so that 591 tumors comprised the final analyses. Discordance was defined as a discrepancy between immunohistochemical and MSI analysis. Problem was defined as indeterminate or questionable immunohistochemical or MSI results. All results and clinical and family histories were centrally reviewed by two pathologists and one genetics counselor. Discordances and problems were identified in 23 of 591 (3.9%) of the tumors. Twelve of 102 MSI-high carcinomas (11.8%) and one of 489 microsatellite stable tumors had discordant immunohistochemistry. Of these 13 tumors, 11 were from patients who had personal and/or family cancer histories concerning for a germline mismatch repair gene mutation. In addition to discordances, 10 tumors with problematic immunohistochemical profiles were identified. Accurate evaluation of MSI was possible in all tumors. In summary, concordance between immunohistochemistry and MSI was high, particularly for tumors that are microsatellite stable. Greater frequency of test discordance was identified in the tumors that were MSI-high. Thus, a major consequence of the use of immunohistochemistry by itself as a screen is the failure to identify colorectal and endometrial cancer patients who likely have Lynch syndrome. Cancer Prev Res; 5(2); 320–7. ©2011 AACR.

Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

Familial adenomatous polyposis [FAP (OMIM 175100)] is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with a locus on chromosome 6q22.1. This mutation is inherited by family members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon 13–exon 15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.

The emerging role of genetics professionals in forensic kinship DNA identification after a mass fatality: lessons learned from Hurricane Katrina volunteers.

Purpose: To explore the experience of medical genetics professionals who volunteered in the DNA identification efforts after Hurricane Katrina to identify “lessons learned” and plan for future recovery efforts.Methods: A web-based survey was administered to volunteers in the Fall of 2007.Results: Sixty-six individuals (75%) completed the survey. Eighty-six percent volunteered because they felt their skills as genetics professional were needed and 46% desired additional training on the molecular aspects of kinship analysis. Most (97%) reported that they would like to see the genetics community become actively involved in further developing the role of genetics professionals in mass fatality response. All respondents (100%) would volunteer again.Conclusion: Developing a registry of volunteers and educational materials tailored to the needs of genetics professionals should be explored as a mechanism to prepare the genetics community to play an active role in future mass fatality response.

A Familial Adenomatous Polyposis (FAP) patient education conference and its impact on patients and families

Background Individuals with familial adenomatous polyposis (FAP) require increased lifelong surveillance due to the high risk of colorectal cancer and extracolonic features. Despite the existence of well-established surveillance guidelines, studies have shown that lack of patient knowledge is a major hurdle to adherence. Patient education conferences represent an avenue for patients to obtain disease-specific information directly from experts. There is ap aucity of data addressing the educational needs and characteristics of individuals who attend such conferences and the impact on their FAP-related knowledge. Methods Individuals with FAP identified through the institution’s FAP registry and their family members were invited to attend an educational conference. Adult attendees were provided IRB approved baseline and follow-up surveys as part of their conference packets. The paired surveys were matched through the use of a unique survey identifier and contained items pertaining to demographic and clinical history, FAP knowledge, and effectiveness of the conference and presenters. Results Of the 50 conference attendees, 35 (70%) completed baseline assessments, and 32 (64%) completed the postconference counterpart. Respondents’ median age was 51 (range: 24 72), and 66% were female. Nineteen (54%) indicated that they had FAP, of which 12 (63%) had undergone colorectal surgery. Fundic gland polyps, duodenal polyps, and desmoid tumors were present in 9 (47%), 11 (58%), and 3 (16%) affected participants, respectively. Hepatoblastoma, duodenal cancer, and osteomas were reported in 1 individual each. Regarding surveillance, 14 (74%) and 13 (68%) of the affected respondents received upper and lower GI surveillance at least once every 3 years, respectively. Participants indicated that among healthcare professionals, their primary sources of information on FAP were primary care physicians (n=15), surgeons (n=12) and/or genetic counselors (n=13). Additional sources of information included internet based resources (n=32), print materials (n=22), and/or other individuals familiar with FAP (n=27). Respondents scored on average 69% correct on a 14-item measure of FAP-related knowledge prior to the conference; post-conference responses showed a statistically significant increase in mean scores (mean=77%, p<0.05). Thirty-one of post-conference respondents (97%) agreed or strongly agreed with items affirming conference effectiveness. Most attendees stated that the FAP conference provided them with information critical to informed medical decision making. All respondents stated a desire to attend future FAP conferences.

The importance of tumor studies in the initial evaluation for Lynch syndrome: a comparison of MMR positive and negative patients

Methods Patients with loss of MLH1/MSH2 on immunohistochemistry (IHC) or with microsatellite instability (MSI)high tumors were identified in our institutional LS database (February 1992–June 2010). Patients who subsequently underwent MLH1/MSH2 mutation analysis were reviewed. Patients with no identifiable MLH1 germline mutation were excluded if MLH1 promoter methylation was present or not assessed. Patients with variants of uncertain significance were also excluded. Demographics, clinical characteristics, mutational testing, and family histories of patients were analyzed.

Rectal cancer in patients with hereditary nonpolyposis colorectal cancer: Surgical management and survival outcomes

Methods Patients referred to our institution for either primary or recurrent rectal cancer between 1992-2010 were identified based on following inclusion criteria: 1) pathogenic germline mutation in DNA mismatch repair genes (MMR; n=19); 2) germline variants of uncertain significance but tumor studies suggestive of MMR (n=6); 3) suggestive tumor studies but negative germline testing (n=5); and 4) suggestive tumor studies but no germline testing (n=4). Patients were reviewed for clinical characteristics and treatments, and followed to death or last contact.

Rectal cancer in hereditary nonpolyposis colorectal cancer.

e14028 Background: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for 2–3% of all colorectal cancers (CRC) and is characterized by mutations in DNA mismatch repair (MMR) genes. Colon ca...