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Background: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. Methods: The population-based study included individuals diagnosed with CRC between 1998–2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. Results: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13–1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. Conclusion: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.

Lynch syndrome, historically known as hereditary non-polyposis colorectal cancer (Jass, 2006), refers to colorectal and other cancers caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 (Vasen et al, 1999). Approximately 1 in 3000 people in the general population carry a mutation in an MMR gene (Dunlop et al, 2000). These MMR gene mutation carriers are at substantially increased risk of colorectal cancer (CRC) with an estimated cumulative risk to age 70 years between 40% and 70% depending on the carrier's sex and the MMR gene that is mutated (Chen et al, 2006; Jenkins et al, 2006; Senter et al, 2008; Baglietto et al, 2010). Physical characteristics or environmental exposures of the mutation carriers could also modify their risks of developing CRC (Jenkins et al, 2007). Identifying modifiers of CRC risk for carriers of MMR gene mutations is important for understanding carcinogenesis. Identifying potentially protective or harmful and avoidable risk factors also creates opportunities for mutation carriers to reduce their risks of life-threatening diseases. Previous studies have provided evidence for the existence of modifiers of CRC risk for MMR gene mutation carriers. For example, CRC risk for carriers is positively associated with alcohol consumption (Watson et al, 2004) and negatively associated with fruit consumption and dietary fibre intake (Diergaarde et al, 2007). For smoking, CRC risk for carriers is positively associated with current smoking (Diergaarde et al, 2007; Pande et al, 2010), but negatively or not associated with former smoking (Diergaarde et al, 2007; Pande et al, 2010). However, the association between body size and CRC risk for MMR gene mutation carriers is yet to be established. One CRC risk factor for people in the general population is body size, a collective term for body mass index (BMI), waist circumference and height (Dai et al, 2007; Larsson and Wolk, 2007; Moghaddam et al, 2007; Renehan et al, 2008). Previous case–control studies of CRC cases with a family history (therefore, likely to be enriched for MMR gene mutation carriers) compared with population-based controls who were unselected for family history, have shown that current BMI is positively associated with CRC risk (Slattery et al, 2003; Campbell et al, 2007). However, studies that have examined the association between current BMI and the occurrence of tumours with microsatellite instability (MSI), a common characteristic of CRCs caused by MMR defects, have reported no statistically significant associations with this form of disease (Slattery et al, 2000; Campbell et al, 2010). One study that examined the association between BMI and colorectal adenoma risk for MMR gene mutation carriers observed a positive association for males but not females (Botma et al, 2010). Identifying an association of BMI in early adulthood on subsequent cancer risk would be important for MMR gene mutation carriers who learn their mutation status as adults in their 20s, an increasingly common occurrence because of increased systematic testing in the population, with the consequent opportunity to reduce their risk of disease. In this study, we estimated an association between BMI at age 20 years and CRC risk for MMR gene mutation carriers. As a comparison, we also estimated the association for non-carriers to investigate whether BMI has a differential effect on risk for CRC by mutation status.

The autosomal recessive polycystic kidney disease (ARPKD) gene, PKHD1, has been implicated in the genesis or growth of colorectal adenocarcinoma, as a high level of somatic mutations was found in colorectal tumor tissue. To determine whether carriers of a single PKHD1 mutation are at increased risk of colorectal carcinoma, we assessed the prevalence of the commonest European mutation, T36M. First, we assayed a European cohort of ARPKD patients and found T36M was responsible for 13.1% of mutations. We then investigated two European cohorts with colorectal adenocarcinoma versus two control cohorts of similar age and gender. Screening for the most common PKHD1 mutation, T36M, we detected 15:3,603 (0.42%) controls versus 1:3,767 (0.027%) colorectal cancer individuals, indicating that heterozygous PKHD1 mutations are not a risk factor and are protective (p = 0.0002). We also show that the carriage rate for PKHD1 mutations in the European population is higher than previous accepted at 3.2% (1:31 genomes).

Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci

El document inclou una pàgina final amb una correcció (corrigendum). Aquesta, per si sola, té el següent DOI: 10.1038/ncomms9739 i es va publicar al mateix vol. 6., Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P

Smith-Lemli-Opitz syndrome is a rare autosomal recessive disorder characterized by multiple congenital anomalies and various degrees of cognitive deficits. This condition results from a deficiency of 7-dehydrocholesterol reductase, a critical step in cholesterol biosynthesis. Children with Smith-Lemli-Opitz syndrome have frequent infections, particularly of the respiratory tract. Immunodeficiency, however, is not recognized as a part of this metabolic condition. Frequent infections are usually attributed to a decreased patient mobility and reduced respiratory effort secondary to muscular hypotonia and mental retardation, which are often present in affected individuals. We describe a patient with Smith-Lemli-Opitz syndrome and recurrent respiratory infections who was found to have a selective antibody deficiency. The immunological diagnosis was based on an absent immune response to Pneumovax. She also had no immunological response to hepatitis B vaccine and was unable to break down red cells with isoagglutinin B. Therapy with intravenous IgG (IVIG) was initiated. Infections were less severe, although they still occurred in a high frequency after initiation of the IVIG therapy. This finding prompts the need for a higher index of suspicion for an underlying immune deficiency in patients with Smith-Lemli-Opitz syndrome who present with recurrent and chronic infections. Early recognition and appropriate therapeutic interventions may decrease the severity of infections, prevent potentially fatal infections, and eventually improve the quality of life in these patients.

Multivitamin use has been related to a modest reduced risk of colorectal cancer (CRC), but evidence on its use after diagnosis in relation to survival has been limited. Incident, invasive CRC cases were identified through cancer registries from 1997–2008 and enrolled in four population-based sites of the Colon Cancer Family Registry (Fred Hutchinson Cancer Research Center, Cancer Care Ontario, Mayo Clinic, and the Universities of Queensland and Melbourne). At enrollment, a standardized interview ascertained multivitamin use in the year prior to diagnosis. A follow-up questionnaire was administered approximately 5 years after baseline, with 2,586 participants providing information on their multivitamin use at both time points. Survival outcomes were identified through linkage to national death registries. Delayed-entry Cox regression was used to estimate the association between patterns of multivitamin use and overall or CRC-specific survival (Hazard Ratio (HR) and 95% Confidence Interval (CI)), with survival time beginning at the 5-year follow-up survey. Models were adjusted for age at diagnosis, sex, body mass index, smoking history, stage, study center, and number of days from diagnosis to baseline survey. Over a median 4.8 years after the follow-up survey, 397 participants died (103 from CRC). Multivitamin use was common: at the 5-year follow-up, 37% reported continued use since before diagnosis, 12% had initiated use, 17% had discontinued use, and only 34% participants reported never using multivitamins. Compared to never use of multivitamins, continued use was significantly associated with increased subsequent overall survival (HR = 0.71, 95% CI: 0.55–0.91). However, this association did not reach statistical significance for CRC-specific survival (HR = 0.76, 95% CI: 0.47–1.24). No significant association was observed for discontinuing (HR = 0.92, 95% CI: 0.68–1.25) or initiating (HR = 0.80, 95% CI: 0.55–1.13) multivitamin use from baseline to follow-up, compared to never users, though initiating use trended towards increased survival. These findings suggest that continuing multivitamin use after a CRC diagnosis may increase survival; replication and details on the specific micronutrients included are needed.

Studies indicate variant of uncertain significance (VUS) results are challenging for genetic counselors and patients, often resulting in negative patient outcomes. Genetic counselors' current practices regarding VUS are unknown. This study utilized a national survey of genetic counselors (n = 932) to examine current practices and confidence related to disclosing BRCA VUS results and reclassification information. For participants (n = 398), descriptive statistics were calculated regarding patient demographic characteristics, practices and confidence, and cross tabulation was used to identify participant's actions when receiving a reclassified VUS. Upon receiving a BRCA VUS report, the majority reported providing patients with information about the frequency with which their VUS was seen and patient ancestry, but a minority discussed DNA banking. Most were confident in their understanding of, and ability to explain, VUS results to patients, but felt less confident about achieving high levels of patient understanding. Upon reclassification, the majority reported calling the patient and mailing the results, but when the reclassification was deleterious, the majority also met with the patient face-to-face. Given the lack of standard professional guidelines about informing patients of initial and reclassified VUS results, this overview provides important insight into genetic counselors' current practices and confidence.

Background: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases. Methods: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. Results: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. Conclusions: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

Approximately 10% of all renal cell carcinomas (RCCs) present a distinctive papillary histology. Familial papillary RCC (PRCC) has been described, but the majority of cases appear to be sporadic. Recently, germline mutations in the MET proto-oncogene on chromosome 7 have been identified in families with hereditary PRCC. We evaluated 59 patients with PRCC for the frequency of MET germline mutations to determine the value of genetic screening of this patient population. Between 1976 and 1997, 165 patients were identified with PRCC by retrospective chart review. Fifty-nine of 133 surviving patients agreed to provide a family history, a blood specimen, and informed consent for genetic research. DNA was isolated from peripheral blood leukocytes. Denaturing high-performance liquid chromatography (DHPLC) followed by genomic sequencing was performed on eight exons of the MET proto-oncogene, including exons 5-7 of the extracellular domain, exon 14, and exons 16-19 of the tyrosine kinase domain. The 59 patients in this study included 49 men and 10 women with a mean age at diagnosis of 61 years. Bilateral and/or multifocal disease was present in 13 cases (22%). No germline mutations were detected in the studied exons of the MET proto-oncogene (exons previously reported to contain deleterious mutations in familial PRCC). No pathological MET proto-oncogene germline mutations were identified in 59 patients with PRCC. The germline mutation rate in this clinic-based population of individuals with PRCC approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutation screening does not appear to be clinically indicated in patients with PRCC without additional evidence for a genetic predisposition (positive family history, unusual age at onset, bilateral disease).

Twenty percent of colorectal cancers (CRCs) arise in people who have a family history of CRC in at least one other relative. Although a fraction of these CRCs are explained by two well-described autosomal dominant syndromes-5% by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial adenomatous polyposis (FAP)-the cause of the remaining 14% of familial aggregates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatellite instability (MSI), and most cases of FAP are caused by germline APC mutations. To date, non-FAP familial CRC aggregates have not been evaluated for germline APC mutations. In this study, we examined the involvement of germline APC mutations in 79 individuals with CRC who had early-age onset of their cancer (age G (proline --> proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were detected: IVS2-53t-->c in 3 cases; IVS4-17ins T in 3 cases; IVS5+32t-->c in 16 cases; and IVS5+33g-->a in 1 case. All appeared to be polymorphisms present in similar proportions in an average-risk population. We conclude that germline APC mutations do not account for familial MSS (stable microsatellite) CRC associated with few synchronous polyps.

Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation.Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods.A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed.Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a newly described, rare autosomal dominant syndrome, characterized by fundic gland polyposis with occasional hyperplastic and adenomatous polyps. We diagnosed GAPPS in a large Australian (Family 1) and two smaller North American families (Family 2 and 3). Mutations in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11 and PTEN were excluded in all families by sequence analysis of exons and flanking regions, as well as by assays for deletion or duplication of exons. We mapped the GAPPS gene in Family 1 by linkage analysis (LOD score 4.21) to a 20Mb region which contains about 60 genes. Short tandem repeat genotyping showed that the affected members of Family 2 share a haplotype in this 20Mb region, but analysis of Affymetrix SNP 6.0 data from three affected members of Family 2 showed that they also shared several other regions of the genome. However, both Family 2 and 3 are too small for definitive linkage analysis. We have carried out full exome sequencing for three affected individuals in Family 1 (and targeted sequencing of the linked region in another individual), and of three affected members of Family 2. We did not find any rare coding or splice site variants in the linked region that were shared by all affected members of Family 1; nor any from the same region in both affected members of Family 2. All coding exons and miR genes in the linked region have been sequenced at least 30X at every base, or by Sanger sequencing, except for seven exons for which Sanger sequencing is yet to be completed. We will also use Sanger sequencing to improve the coverage of exons in the linked region in Family 2. However, our current hypothesis is that non-coding mutations in the linked region are responsible for the GAPPS syndrome in both Families 1 and 2 and so whole genome sequence analysis for two affected members in Family 1 has been performed and analysis is underway.

Objective Pirfenidone (Deskar, Marnac Inc., Dallas, TX), 5-methyl-1-phenyl-2-(1H)-pyridone, is a broad-spectrum, noncytotoxic, oral antifibrotic agent that is reported to inhibit or block the action of cytokine growth factors: transforming growth factor β1, platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor, and to prevent formation of new fibrotic lesions. Methods We enrolled 10 women and four men with extensive familial adenomatous polyposis (FAP)-associated desmoid disease in a 2-yr open-label treatment trial with oral pirfenidone. Imaging of desmoids was conducted at baseline and 6, 12, and 24 months. Results No drug toxicity or drug intolerance was encountered. Seven patients dropped out (three because of progressive disease), and seven continued for at least 18 months. Of those that continued, two had partial but significant reduction in the size of all desmoids beginning in the first 6 months of treatment, and two others experienced relief of symptoms without change in desmoid size. Three patients experienced no change in tumor size or symptoms. Conclusion Pirfenidone is well tolerated by patients with FAP-associated desmoid tumors. Some patients with FAP/desmoid tumors treated with pirfenidone had regression of tumors, some had progression, and some had no response. Patients with rapidly growing tumors did not respond to pirfenidone. A placebo-controlled trial is needed to determine whether there is a subset of patients for whom pirfenidone may result in partial shrinkage of desmoid tumors, because the natural history of desmoid tumors is not predictable or understood.

The CDH1 gene encodes E-cadherin, an epithelial cell adhesion molecule. Germline CDH1 mutations recently were identified in families with hereditary diffuse gastric carcinoma in a pattern suggestive of autosomal dominant inheritance with incomplete penetrance.The proband was a woman age 47 years with a strong family history of diffuse gastric carcinoma. A germline E-cadherin gene mutation was identified in this patient, her brother, and three first cousins. All five family members underwent endoscopic evaluations, which were negative for malignancy, and elected to undergo a prophylactic total gastrectomy with Roux-en-Y esophagojejunostomy.Pathologic examination of the proband's stomach revealed several microscopic foci of intramucosal signet ring cell adenocarcinoma in the cardia and proximal gastric body. Postgastrectomy specimens from the proband's brother and three first cousins all showed intramucosal signet ring cell adenocarcinoma in various regions of the stomach. Immunoperoxidase studies performed on gastric tissue from these five patients demonstrated diminished or absent E-cadherin reactivity in the cancerous mucosa.Although total gastrectomy was performed as a prophylactic intervention, occult gastric carcinoma was discovered in all five patients. Thus, total gastrectomy should be curative for gastric carcinoma in these patients. Based on their successful outcomes and the lack of efficacious surveillance methods for diffuse gastric carcinoma, prophylactic total gastrectomy may be the management of choice for germline E-cadherin gene mutation carriers. However, prophylactic total gastrectomy should be undertaken cautiously because the procedure may be associated with considerable morbidity.

Twenty percent of colorectal cancers (CRCs) arise in people who have a family history of CRC in at least one other relative. Although a fraction of these CRCs are explained by two well-described autosomal dominant syndromes-5% by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial adenomatous polyposis (FAP)-the cause of the remaining 14% of familial aggregates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatellite instability (MSI), and most cases of FAP are caused by germline APC mutations. To date, non-FAP familial CRC aggregates have not been evaluated for germline APC mutations. In this study, we examined the involvement of germline APC mutations in 79 individuals with CRC who had early-age onset of their cancer (age50 years) and/or a family history of CRC. Cases with FAP or HNPCC due to defective mismatch repair were excluded from the study. Using conformation-sensitive gel electrophoresis and the protein truncation test as the screening methods, no functionally significant germline mutations were detected for any of the cases. An apparently silent polymorphism resulting in a 1-bp alteration of A --G (proline --proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were detected: IVS2-53t--c in 3 cases; IVS4-17ins T in 3 cases; IVS5+32t--c in 16 cases; and IVS5+33g--a in 1 case. All appeared to be polymorphisms present in similar proportions in an average-risk population. We conclude that germline APC mutations do not account for familial MSS (stable microsatellite) CRC associated with few synchronous polyps.

Rothmund-Thomson syndrome (RTS), an autosomal recessive disorder, comprises poikiloderma, growth deficiency, some aspects of premature aging, and a predisposition to malignancy, especially osteogenic sarcomas. Two kindreds with RTS were recently shown to segregate for mutations in the human RECQL4 helicase gene. We report identification of a new RTS kindred in which both brothers developed osteosarcomas. Mutation analysis of the RECQL4 gene was performed on both brothers and both parents. The brothers were shown to be compound heterozygotes for mutations in the RECQL4 gene, including a single basepair deletion in exon 9 resulting in a frameshift and early termination codon and a base substitution in the 3-prime splice site in the intron-exon boundary of exon 8, which would be predicted to cause a deletion of at least part of a consensus helicase domain. Each parent was shown to be a heterozygote carrier for one mutation. This report strengthens the association between mutations in RECQL4 helicase gene and RTS. Two other recessive disorders, Bloom syndrome and Werner syndrome, are known to be due to other human RECQ helicase gene mutations. These three disorders all manifest abnormal growth, premature aging, and predisposition to site-specific malignancies. The clinical and molecular aspects of RTS, Bloom syndrome, and Werner syndrome are compared and contrasted.

The 3p- syndrome results from deletion of a terminal segment of the short arm of one chromosome 3 (3p25--pter), and is characterized by multiple congenital anomalies and mental retardation. Due to its variable expression, it is assumed this disorder is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to discover genes contributing to mental defects in 3p- syndrome, we determined whether the CALL gene, mapped to 3p26.1 and coding for a neural recognition molecule, is deleted in a boy with this disorder. We found that the break in this patient is distal to the VHL gene, removing D3S18 and the CALL loci. The deletion of one copy of the CALL gene might be responsible for mental defects in patients with 3p- syndrome. Am. J. Med. Genet. 86:482-485, 1999. Published 1999 Wiley-Liss, Inc.

To extend earlier observations of germline E-cadherin mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, we searched for germline E-cadherin mutations in five further families affected predominantly by diffuse gastric cancer and one family with a history of diffuse gastric cancer and early-onset breast cancer. Heterozygous inactivating mutations were found in the E-cadherin gene in each of these families. No mutation hotspots were identified. These results demonstrate that germline mutation of the E-cadherin gene is a common cause of hereditary diffuse gastric cancer and suggest a role for these mutations in the incidence of breast cancer.

Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD with LC, few studies examined the association of alpha1AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with70 variants reported. There are at least 10 alleles associated with deficiency in alpha1-antitrypsin. Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). alpha1AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, Por = 0.01, respectively). Our preliminary findings suggest that individuals who carry an alpha1AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.

We describe a 20-year-old man with Smith-Magenis syndrome and a 46,XY,del(17)(p11.2p11.2) karyotype. The interstitial deletion was confirmed by metaphase analysis using the fluorescent in situ hybridization probe (D17S29) for the Smith-Magenis region. The patient had hypertelorism, exotropia, and high myopia. Examination under anesthesia showed a lacquer crack near the right macula and a disciform scar of the left macula. Six months later, the patient presented with subacute visual loss. Examination demonstrated end-stage macula degeneration with bilateral disciform scars. There was no evidence of retinal detachment. Prior reports of Smith-Magenis syndrome mention telecanthus, ptosis, strabismus, iris anomalies, cataract, microcornea, optic nerve hypoplasia, myopia, retinal detachment, and lattice retinal degeneration. Bilateral macular degeneration has not been reported previously, and it may be an additional ophthalmologic manifestation of Smith-Magenis syndrome, either as a primary manifestation or as a direct consequence of high myopia.

We describe a child with alpha-thalassemia ascertained by newborn screening. Evaluation at 9 months of age showed minor anomalies and developmental delay. Chromosomal analysis demonstrated a de novo deletion of the most distal portion of the short arm of chromosome 16, which contains the alpha-globin genes. Analysis of the alpha-globin locus by Southern blot analysis did not demonstrate altered band sizes at this locus; however, analysis of the films using densitometry confirmed hemizygosity. This is the fifth reported case of the ATR-16 syndrome (alpha-thalassemia retardation-16) not complicated by duplication or deletion of other chromosomes.

We report on a 40-year-old woman with melorheostosis who also had radiographic findings of generalized osteopoikilosis. Three of her sibs have osteopoikilosis, but none of them have melorheostosis. Several cases of "mixed sclerosing bone dysplasia" have been described previously, and all have been sporadic. Isolated melorheostosis without osteopoikilosis is also generally a sporadic condition, but osteopoikilosis has been described as an autosomal-dominant trait. The finding of mixed sclerosing bone dysplasia in a family with osteopoikilosis suggests that the melorheostotic component of this disorder may be due to a second mutation at the same locus that causes isolated familial osteopoikilosis.

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.

A two and a half-year-old girl was diagnosed with trisomy 9 mosaicism that was detected in 22% of skin fibroblasts but was not evident in blood. This child manifests some clinical features not previously reported in trisomy 9 mosaicism including a thoracic syringomyelia and a tethered cord due to an extradural lipoma with intradural involvement. DNA analysis showed that she did not have uniparental disomy in her dominant disomic cell line.

Methods We studied 167 MLH1 and 225 MSH2 mutation-carrying families comprising 17,352 members from the Colon Cancer Family Registry. Probands were recruited either because they had a family history of cancer (n=274) or from cancer registries independently of family history (n=118). Hazard ratios (HRs) of cancer risks for carriers compared with the general population and age-specific cumulative risks for carriers (penetrance) were estimated using modified segregation analysis conditioned on ascertainment. Heterogeneity in risks for carriers was modelled with a polygenic risk modifier (as in the BOADICEA model).

Background It is known that metachronous colorectal cancer risk for Lynch syndrome patients with primary colon cancer is high and total colectomy is the preferred option [1]. However if the index primary cancer is in the rectum, management advice is complicated by considerations of worsening bowel function or stoma formation. To aid surgical decision-making, we estimated the risk of metachronous colon cancer for Lynch syndrome patients who underwent either anterior resection or abdominoperineal resection for primary rectal cancer.

3538 Background: Lynch syndrome is caused by a germ-line mutation in a DNA mismatch repair (MMR) gene. Carriers are at high risks of colorectal (CRC), endometrial and some other cancers. To date, t...

1521 Background: Women with an inherited mutation in a mismatch repair (MMR) gene have a substantially increased risk of endometrial cancer (EC) during their lifetime. In the general population, ri...

3515 Background: Appropriate surgical management of colorectal cancers (CRC) in Lynch syndrome patients, i.e., carriers of a mutation in a mismatch repair (MMR) gene, is still controversial. The de...

1501 Background: Lynch syndrome, a hereditary cancer syndrome characterized by germline mutations in mismatch repair (MMR) genes, is associated with an elevated lifetime risk of cancer development, predominantly endometrial, colorectal and ovarian. To date, no increased risk of cervical cancer for mutation carriers has been reported. Methods: Families with an identified pathologic mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2 were obtained from Colon Cancer Family Registry (Australasia, USA and Canada). Families were ascertained via a population- based colorectal cancer case or via family cancer clinics. Attempts were made to obtain pathology reports for cases of cervical cancer. Modified segregation analyses incorporating rigorous corrections for ascertainment were used to estimate relative and cumulative risks of cervical cancer for mutation carriers. Binomial tests and t-tests and were used to compare observed histology and ages of diagnosis to population norms. Results: A total of 66 cases...

A patient was evaluated with familial trigeminal neuralgia (TN) and contralateral hemifacial spasm. The mother of the patient, 5 of 10 siblings, and 1 nephew also had TN confirmed by neurologists. The transmission of TN was suggestive of an autosomal dominant inheritance. This family provides additional evidence of a genetic basis for TN in selected cases and also provokes further speculation on a common unifying hypothesis of pathophysiology in cranial rhizopathies.