Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: a retrospective study in a sample of Italian cancer genetics clinics.

PURPOSE: To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing. PATIENTS AND METHODS: The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008. RESULTS: 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers. CONCLUSION: Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment.

Double pituitary adenomas.

Double pituitary adenomas represent up to 2.6 % of pituitary adenomas in large surgical series and up to 3.3 % of patients with Cushing's disease have been found to have double or multiple pituitary adenomas. We report the case of a 60-year-old male patient whose medical history began in 2002 with erectile dysfunction; hyperprolactinemia was found and MRI showed a 6-mm area of delayed enhancement in the lateral portion of the right pituitary lobe. Treatment with cabergoline was started with normalization of prolactin levels; the following MRI, performed in 2005 and 2008, showed shrinkage of the pituitary lesion. In 2005, the patient began to manifest weight gain, hypertension, and facial plethora, but no further evaluations were done. In January 2010, the patient came to our attention and underwent multiple tests that suggested Cushing's disease. A new MRI was negative. Bilateral inferior petrosal sinus sampling showed significant pituitary-to-peripheral ratio and, in May 2010, the patient underwent exploratory pituitary surgery with evidence of a 1-2-mm white-coloured midline area compatible with pituitary adenoma that was surgically removed. Post-operatively, the patient's clinical conditions improved with onset of secondary hypoadrenalism. The histologic examination confirmed a pituitary adenoma (immunostaining was found to be positive for ACTH and negative for prolactin). We report the case of an ACTH-producing microadenoma metachronous to a prolactin secreting microadenoma although not confirmed histologically, shrunk by medical treatment. A review of data in the literature regarding double or multiple pituitary adenomas has also been done.

The Simpson-Golabi-Behmel syndrome: A clinical case and a detective story.

The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth condition comprising "coarseness" of facial traits, supernumerary nipples, congenital heart defects, polydactyly and fingernail hypoplasia, and an increased risk of neonatal death and later neoplasia. Psychomotor development is usually normal. The syndrome is caused by mutation/deletion of the X-linked gene GPC3. We describe a new case of SGBS, that led to the discovery of an extended family segregating a GPC3 mutation and, ultimately, of an affected relative forgotten, but not lost, in an anatomical museum, where he was classified as a macrosomic newborn, who was born probably around 1940 and died neonatally of unknown cause. This baby boy becomes the oldest case of SGBS on record.

Frequency of constitutional MSH6 mutations in a consecutive series of families with clinical suspicion of HNPCC.

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC.

A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer.

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.

Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.

Familial microsatellite-stable non-polyposis colorectal cancer: incidence and characteristics in a clinic-based population.

BACKGROUND: About 15%-20% of colorectal cancers (CRCs) are familial. While a fraction of these arise in the context of hereditary syndromes, the causes underlying the majority of familial CRCs are not yet understood. PATIENTS AND METHODS: Family history of cancer, clinical characteristics, and microsatellite instability (MSI) in a series of 100 consecutive CRC patients were evaluated. RESULTS: Eighteen patients had a positive family history of CRC in a first-degree relative. Of these, two had a clinical diagnosis of familial adenomatous polyposis (FAP), and three were diagnosed with hereditary non-polyposis colorectal cancer (HNPCC) following results of MSI analysis. A diagnosis of HNPCC was also established in a fourth patient with early onset CRC, who had a second-degree relative with CRC, and whose tumor was positive for MSI. The remaining 13 familial CRCs did not show MSI in tumor DNA. The mean age at tumor diagnosis in patients with familial microsatellite-stable (MSS) CRC was higher than in HNPCC and FAP patients and similar to that recorded in sporadic cases. The incidence of second primary malignancies was significantly higher in familial MSS CRC probands (n = 4) compared to patients who did not have a diagnosis of FAP or HNPCC and did not have first-degree relatives affected with CRC (n = 6, in a total of 81 probands with these characteristics). CONCLUSIONS: These results define the existence of a subset of familial CRCs characterized by relatively late age at onset, high incidence of second primary tumors, and absence of MSI in tumor DNA.

Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer.

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing.

Hereditary nonpolyposis colorectal cancer: an approach to the selection of candidates to genetic testing based on clinical and molecular characteristics.

OBJECTIVE: Identification of clinical and molecular characteristics associated with constitutional MLH1 and MSH2 mutations and definition of a stepwise strategy for the selection of colorectal cancer (CRC) patients amenable to MLH1 and MSH2 genetic testing. METHODS: 90 unrelated CRC patients were initially selected on the basis of either familial or early onset occurrence of CRC. They were screened for the presence of constitutional MLH1 and MSH2 mutations and for microsatellite instability (MSI). RESULTS: 16 pathogenetic mutations (9 MLH1 and 7 MSH2) were identified in 41% of Amsterdam hereditary nonpolyposis colorectal cancer (HNPCC) families, 5% of suspected HNPCC families, and 14% of sporadic early-onset CRC patients. The presence of the mutations correlated with MSI, with early age of onset and proximal location of the tumor, and with the presence of some extracolonic tumors of the HNPCC spectrum and/or multiple tumors in the family. CONCLUSIONS: Evaluation of clinical and molecular characteristics is useful for the identification of candidates to MLH1 and MSH2 mutational analysis and allows the application of a rational approach to genetic testing.