Emily Glogowski

MSH6 germline mutations are rare in colorectal cancer families

Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease‐causing mutations of MSH6 may or may not exhibit MSI. We used D‐HPLC to screen for germline mutations in the promoter region, the coding region and the 3′‐UTR of MSH6. Eighty‐four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC‐like families), were tested for MMR gene mutations; 27 families had a disease‐causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein‐truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early‐onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease‐causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease‐causing germline mutations of MSH6 are rare in HNPCC and HNPCC‐like families.

A636P is associated with early-onset colon cancer in Ashkenazi Jews

BACKGROUND Hereditary predisposition to colorectal cancer most often manifests itself as familial adenomatous polyposis from mutations of APC, or hereditary nonpolyposis colorectal cancer, resulting from mutations of MSH2, MLH1, MSH6, or other genes. Previously, we described a rare founder mutation MSH2*1906C > G in Ashkenazi Jews that was found in 8 of 1,345 individuals (0.6%) of Ashkenazi descent with colorectal cancer. This study seeks to characterize the proportion of individuals of Ashkenazi heritage with very early-onset colon cancer (diagnosed at age 40 or younger) that could be attributed to MSH2*1906C>G. STUDY DESIGN We analyzed the carrier frequency of MSH2*1906C>G in paraffin samples from 31 Jewish patients age 40 or less, diagnosed with colorectal cancer at Memorial Sloan-Kettering and lymphocyte-derived DNA from 10 patients. We did not select for family history. Genotyping for MSH2*1906C>G was performed by polymerase chain reaction and restriction enzyme digestion methods. RESULTS We detected the MSH2*1906G>C mutation in 3 of the 41 samples (7.14%) of patients who had colorectal cancer diagnosed at age 40 or younger. This incidence is significantly greater than the 8 in 1,345 (0.6%) we observed for cases of colorectal cancer in Ashkenazi Jews not selected for age (p = 0.004). CONCLUSION Although very rare in the population, MSH2*1906G>C is found at an increased frequency in young Jewish patients with colorectal cancer. These results suggest that testing for the MSH2*1906G>C mutation should be included in the evaluation of Ashkenazi Jewish individuals diagnosed with early-onset colon cancer.

Sources of uncertainty about daughters' breast cancer risk that emerge during genetic counseling consultations.

Uncertainty is central to the experience of genetic decision making and counseling about cancer risk. Women seeking genetic counseling about their breast cancer risk may experience a great deal of uncertainty about issues related to their daughters. We used a theory of Communication and Uncertainty Management to guide analysis of sources of uncertainty about daughters that emerged during 16 video-recorded and transcribed conversations between mothers at risk for a BRCA 1/2 mutation and their genetic healthcare practitioners. An interpretive design and constant comparative method revealed three dominant patterns or themes representing sources of uncertainty mothers have relating to their daughters: disease risk, future cancer screening, and communication of related information to daughters. Both practitioners and mothers discussed these aspects of uncertainty. The findings identify the significant role uncertainty and familial concerns play in mothers’ genetic testing decision making process. To assist genetic practitioners, we highlight daughter-related concerns that mothers are uncertain about and which are vital to their genetic counseling needs.

Insurance reimbursement for risk-reducing mastectomy and oophorectomy in women with BRCA1 or BRCA2 mutations

Purpose: Risk-reducing surgery is an important option for women with BRCA1 and BRCA2 mutations. There are reports in the literature that insurance reimbursement for these procedures varies greatly. Because health insurance coverage significantly affects medical decision-making, current information regarding reimbursement practices of third-party payers is needed.Methods: Retrospective study of hospital billing records of 38 women with documented BRCA1 or BRCA2 mutations who underwent either a risk-reducing mastectomy or a risk-reducing oophorectomy between March 1, 1997, and July 30, 2000.Results: Complete billing and reimbursement information was available for 35 women undergoing a total of 39 risk-reducing surgeries. A total of 38 of 39 (97%) risk-reducing surgeries were covered in full, less applicable coinsurance and deductibles. The rate of insurance reimbursement did not vary with type of insurance, personal history of cancer, or type of procedure.Conclusion: Insurance carriers reimbursed the vast majority of BRCA mutation carriers undergoing risk-reducing surgery.

Preliminary validation of a consumer-oriented colorectal cancer risk assessment tool compatible with the US Surgeon General’s My Family Health Portrait

Purpose:This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General’s My Family Health Portrait (MFHP).Methods:An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with “gold standard” risk assessments developed by three expert cancer genetic counselors.Results:Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54–96%) and specificity of 90% (95% confidence interval: 83–94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29–68%), whereas the negative predictive value was 98% (95% confidence interval: 93–99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54).Conclusion:The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753–756.

Talking About Familial Breast Cancer Risk Topics and Strategies to Enhance Mother–Daughter Interactions

A hereditary cancer predisposition can rattle families, creating dysfunctional interactions. Families need assistance navigating conversations about risk. Because mothers and daughters uniquely share breast cancer experiences and risk, there is a particular need for practitioners to assist them with communication. Three focus groups were conducted with 11 mothers with an elevated cancer risk (with adolescent daughters) receiving genetic counseling. We explored three inquiries to capture mother–daughter communication: emergent challenging topics (e.g., health-promotion behavior, daughter’s risk, mother’s risk of death), factors complicating discussions (e.g., balancing what to share and when, guilt and blaming, confusion about risk and prevention), and strategies enhancing conversations initiated by mothers (e.g., paying attention to daughter’s cues) or practitioners (e.g., inviting daughters to appointments). Findings suggested that mothers struggle to balance eliciting daughters’ concerns, providing them with support, and imparting knowledge without overwhelming them. We offer mothers and practitioners guidance to help facilitate these conversations.

Single-amplicon MSH2 A636P Mutation Testing in Ashkenazi Jewish Patients With Colorectal Cancer: Role in Presurgical Management

Objective:This study summarizes our initial experience with prospective, single-amplicon (mutation-specific) A636P testing in Ashkenazi Jewish patients at risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Summary Background Data:We previously described a founder mutation, MSH2*1906G >C (A636P) that causes HNPCC in 8/1345 (0.59%) of Ashkenazim with colorectal cancer. The mutation was more common in Ashkenazim diagnosed at ≤40 years (7%). Methods:Twenty-seven Ashkenazi probands at risk for HNPCC were ascertained. Single-amplicon A636P testing was performed on 21 by polymerase chain reaction of exon 12 of MSH2, followed by direct DNA sequencing. Mutational analysis of the entire open reading frame of MLH1 and MSH2 was performed on 7 by PCR of each exon, followed by heteroduplex analysis using denaturing high-performance liquid chromatography and direct sequencing of exons with variant chromatographs. One patient received both studies, Results:The A636P mutation was detected in 3/21 (14%) prospectively evaluated patients using single amplicon testing. In 6 patients, the entire open reading frame of MLH1 and MSH2 was analyzed, and 1 additional A636P carrier and 2 carriers of previously unrecognized mutations were identified. The A636P mutation was present in 2 patients who met Amsterdam criteria and in 2 patients who did not. Conclusions:Although rare in the general population, A636P mutations are found at increased frequency in Ashkenazim with a personal or family history of colorectal or other HNPCC-associated cancers. This inexpensive and rapid approach may be useful preoperatively in helping determine the extent of colon resection for a subset of patients.

Outcome of genetic evaluation of patients with kidney cancer referred for suspected hereditary cancer syndromes

OBJECTIVE To analyze patients with kidney cancer referred for evaluation at a high-volume genetics service at a comprehensive cancer center and identify factors associated with positive tests for hereditary cancer syndromes. METHODS A retrospective review of patients referred to the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center was performed, and patients with a personal history of kidney cancer were identified. Patient and disease characteristics were reviewed. In all, 4 variables including age at diagnosis of kidney tumor, presence of syndromic manifestations, family history of kidney cancer, and number of primary malignancies were evaluated for association with positive test results in 2 groups: patients tested for renal cell carcinoma syndromes and Lynch syndrome. Guidance for genetic testing strategy in patients with kidney cancer is provided. RESULTS Between 1999 and 2012, 120 patients with a history of kidney cancer were evaluated by the Clinical Genetics Service. The mean age at kidney cancer diagnosis was 52 years (interquartile range: 42-63), with 57% being women. A family history of kidney cancer was reported by 39 patients (33%). Time between diagnosis of first cancer and genetic consultation was <1 year in 54%, 2 to 5 years in 23%, and>5 years in the remaining 23%. Overall, 95 patients were tested for genetic abnormalities with 27 (28%) testing positive. Testing for renal cell carcinoma (RCC)-related syndromes was performed on 43 patients, with 13 testing positive (30%). Lynch syndrome testing was positive in 9 patients (32%) after 28 were tested. In RCC-associated syndromes, young age of diagnosis was associated with positive test results. Conversely, syndromic manifestations and increasing number of primary malignancies were associated with positive Lynch testing. CONCLUSIONS The discovery of inherited kidney cancer syndromes has provided a unique opportunity to identify patients at increased risk for cancer. Factors associated with positive genetic testing are unique to different syndromes. These data suggest that in kidney cancer patients evaluated for hereditary cancer syndromes, young age is associated with diagnosis of RCC syndromes, whereas syndromic manifestations and multiple primaries are found in Lynch syndrome. These results, along with clinical awareness, may be useful for practicing urologists to select patients with kidney cancer to refer for genetic counseling.

Prospective Immunohistochemical Analysis of Primary Colorectal Cancers for Loss of Mismatch Repair Protein Expression

BACKGROUND Evaluation of patients for Lynch syndrome includes assessment of age and family cancer history as well as testing for microsatellite instability and alterations in mismatch repair (MMR) genes. We examined the value of routine immunohistochemistry (IHC) for MMR proteins in patients with colorectal cancer (CRC) undergoing resection at a single institution. PATIENTS AND METHODS Beginning in July 2006, all patients aged < 50 years who were undergoing resection of primary CRC had their specimens routinely examined by IHC for MMR proteins. Patients aged 50-60 years were examined if histopathology suggestive of Lynch syndrome was reported, and patients of any age were examined if strong clinical suspicion was present. Family cancer history was analyzed and fulfillment of Amsterdam II criteria determined. RESULTS Over an 18-month period, 96 patients aged < 50 years underwent CRC resection. Out of these, 72 patients (75%) had immunohistochemical testing, with an overall MMR protein loss rate of 19%. In selected patients aged 50-60 years and > 60 years, loss rates were 26% and 65%, respectively. Of all patients with MMR protein loss, 10 (32%) had reported histopathology, and 3 (10%) had family histories suggesting Lynch syndrome. CONCLUSION We demonstrate the feasibility of routine immunohistochemical testing for MMR proteins in patients with CRC. As only a minority of patients with MMR protein loss met Amsterdam II criteria or had suggestive histopathology reported, routine IHC may identify patients with Lynch syndrome who might otherwise be missed.

MP36-06 UTILITY OF PROSPECTIVE PATHOLOGIC EVALUATION TO INFORM CLINICAL GENETIC TESTING FOR HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA

INTRODUCTION AND OBJECTIVES: Hereditary leiomyomatosis and renal cell cancer (HLRCC) resulting from fumarate hydratase (FH) mutations may present with skin, uterine, and renal tumors each with unique pathologic features. These characteristic features, when recognized during pathology assessment of surgical specimens may prompt further clinical investigation. We evaluated the association between suspicious pathology (SP) and positive results from patients referred for subsequent genetic testing. METHODS: In an IRB approved study we identified patients who underwent FH testing during a clinical genetic evaluation from 2008-2013. Tested-relatives of HLRCC probands were excluded. We defined SP as specific report of HLRCC histologic features identified during pathologic assessment prospectively. FH testing for all patients was performed in a CLIA-certified laboratory. We analyzed clinicopathologic data in those withand without-SP and the association between SP and FH mutation using Mann-Whitney test and Fisher’s exact test. RESULTS: 29 patients comprised the study cohort; median age was 37 years (IQR 31, 49), 15 (52%) were female, and 18 (62%) were Caucasian. 39 associated pathologic specimens were identified. Pathologists reported SP in 23 of the 39 specimens (59%) from 21 of 29 patients (72%). SP positive specimens included: kidney tumor (11/18), leiomyoma [(9/15) uterine (8) and bladder (1)], and metastatic tumors (3/6). Patients with SP were younger (35 vs. 51, p1⁄40.010) and more often had stage pT3 RCC (100% vs 33%, p1⁄40.006) compared to those without SP. FH mutation was present in 8 (38%) with SP and 1 (13%) without SP (p1⁄40.37); 7 of these had kidney cancer (SP1⁄47), all with N1 disease, and 2 had only uterine leiomyoma (SP1⁄42) combined with diagnostic skin leiomyomas. Analyzing SP by tissue type identified only SP from renal tumors as significantly associated with positive testing for FH mutation (p1⁄40.013). Leiomyoma SP had 70% false positives; however 1 case led to diagnosis of skin leiomyomas and FH mutation. Genetic screening in FH+ patients identified 5 relatives also with germline FH mutation who are under surveillance. CONCLUSIONS: Only SP from kidney tumors undergoing routine pathologic assessment was significantly associated with FH mutation although identification from other tissues is possible and may prompt thorough investigation. This mechanism may be vital for identification of syndromic HLRCC cases and initiation of potentially lifesaving screening strategies.