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.     

Early onset renal cell carcinoma in an adolescent girl with germline <Emphasis Type="Italic">FLCN</Emphasis> exon 5 deletion

Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30–45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.     

Professional Challenges in Cancer Genetic Testing: Who Is the Patient?

In the genetic counseling setting, the health care provider can be challenged by opposing duties to members of the same family: protecting the privacy of the patient identified with a gene mutation and the ethical obligation to warn at-risk relatives. In a situation of nondisclosure between members of a family with a known disease-predisposing mutation, this type of dilemma can present in acute form for the provider who cares for different members of the family. This can hinder effective medical decision making. To minimize this effect, we recommend detailed pretest genetic counseling steps to empower the patient to communicate with their at-risk relatives their intent to pursue testing and willingness to share information. In addition, post-test counseling should reiterate the implications of a positive result for at-risk relatives and conclude with a written summary that patients can share with their family.     

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

Carboxypeptidase E (CPE) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. One of the features of type 2 diabetes mellitus (T2DM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio, suggesting that mutations in proinsulin processing enzymes may contribute to the development of T2DM. We scanned CPE for mutations in a collection of Ashkenazi T2DM families and identified five novel single nucleotide polymorphisms (SNPs). An SNP in the 283^rd codon, c.847C>T, changes arginine to tryptophan (R283W). The residue Arg283 is conserved among CPE orthologs as well as most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi T2DM pedigrees screened, we found four families segregating R283W. Within these four families, patients who inherited one copy of this variant had much earlier age of onset for T2DM. The R283W CPE protein cleaves peptide substrates with substantially lower efficiencies and is less stable at elevated temperature. In addition, the R283W CPE variant has a narrower pH optimum and is much less active at pH 6.0–6.5, indicating that the R283W CPE variant would be substantially less active than wild type CPE in the trans‐Golgi network and immature secretory vesicles where the enzyme functions in vivo. To summarize, we uncovered a rare non‐conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties. We predict that this mutant could cause hyperproinsulinism and diabetes in the homozygous state. Hum Mutat 18:120–131, 2001. © 2001 Wiley‐Liss, Inc.     

Uptake of BRCA1 rearrangement panel testing: in individuals previously tested for BRCA1/2 mutations.

PURPOSE: Individuals undergoing genetic testing for BRCA1/2 mutations are routinely counseled about the sensitivity and specificity of testing. In August 2002, testing for 5 large genomic rearrangements in the BRCA1 gene that would not have been detected with full gene sequence analysis became commercially available. We present our data on uptake of the BRCA1 rearrangement panel testing in our clinical cancer genetics program. METHODS: Women who participated in our clinical genetic testing program and had previously received an uninformative negative or variant of uncertain significance result from BRCA1/2 full gene sequencing were invited to consider BRCA1 rearrangement panel testing. RESULTS: Overall, 18/72 individuals underwent BRCA1 rearrangement panel testing. No significant differences were found in the levels of BRCAPRO scores (P = 0.406), age at testing (P = 0.986), number of children (P = 0.35) or number of siblings (P = 0.4) between individuals who chose to pursue additional testing with the rearrangement panel and those who declined. Fisher's Exact Test analysis showed that there is a negative association between having breast or ovarian cancer and being inclined to undergo rearrangement panel testing (P = 0.013). CONCLUSION: Individuals who undergo genetic testing will not consistently pursue additional or enhanced genetic testing. Future research is needed to clearly elucidate the factors associated with uptake of additional genetic testing.     

Assessment of clinical practices among cancer genetic counselors

Various models of cancer genetics service delivery have been published, and practice guidelines were set forth by the National Society of Genetic Counselors (NSGC) in 2004. While the demand for services has increased, there has not been a comprehensive study of current practice models. An online survey of the NSGC Familial Cancer Risk Counseling Special Interest Group was conducted to study current methods of providing clinical cancer genetics services. Respondents were asked to quantify patient volume, support staff availability, and physician involvement in cases. Two case examples were used to further describe current practices including the number of genetic counseling tasks performed, time spent in these tasks, and number of in-person visits versus phone encounters. Although published cancer genetic counseling guidelines advise a 3-visit model (initial consult, sample draw, and result disclosure), 29.3% of respondents have adopted a 1-visit model, where the sample is drawn at the first visit and phone disclosure replaces the third visit. The content of the initial consult does not vary significantly, and is consistent with the NSGC practice guidelines. Furthermore, 56% report spending >15 min on case preparation, and 27 respondents self-reported redundancy in tasks such as documentation. It appears that a proportion of genetic counselors are following a new model of service delivery. However, insufficient documentation and case preparation are apparent, and many respondents reported lack of support staff as a barrier to efficient patient care. Factors contributing to the variability in current practice, and how they affect efficiency, require further study.     

Which individuals undergoing BRACAnalysis need BART testing?

Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e., BRACAnalysis Rearrangement Test, or BART?) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable.     

Genetic testing by cancer site: urinary tract

ABSTRACT: The roles of renal cell carcinoma (RCC) and urothelial cancers of the upper urinary tract are often overlooked as indicators for genetic risk assessment. The key features of 5 hereditary cancer susceptibility conditions involving an increased risk for RCC are discussed. von Hippel-Lindau disease, hereditary papillary RCC, and hereditary leiomyomatosis and RCC each predispose to a specific histological type of RCC, whereas Birt-Hogg-Dubé and hereditary paraganglioma/pheochromocytoma entail a variety of histologic findings. Familiarity with the rare or uncommon clinical features associated with these conditions, such as cutaneous neoplasms, paraganglioma/pheochromocytoma, and recurrent spontaneous pneumothoraces, aids in identifying patients with an underlying RCC susceptibility. A path to identifying syndromic cases lies in thorough investigation of the patient's medical history, their family history, and the histological type of RCC reported in the family. A guide to genetic predisposition testing for RCC is proposed. Upper urinary tract cancers in Lynch syndrome are also discussed.     

Psychiatric implications of cancer genetic testing

As genetic testing for hereditary cancer syndromes has transitioned from research to clinical settings, research regarding its accompanying psychosocial effects has grown. Men and women being tested for hereditary cancer syndromes may experience some psychological distress while going through the process of testing or after carrier status is identified. Psychological distress appears to decrease over the course of the first year and it is typically not clinically significant. Longer term studies show mixed results with some mutation carriers continuing to experience elevated distress. Baseline distress is the greatest risk factor for both immediate (weeks‐12 months) and long‐term psychological distress (18 mo‐8 years post genetic testing). In addition to baseline psychological distress, other risk factors can be identified to help identify individuals who may need psychosocial interventions during the genetic testing process. The challenges of providing clinical care to the growing population of individuals identified to be at increased risk for heritable cancers present opportunities for research and new models of care. Cancer 2015;121:341–360. © 2014 American Cancer Society.