Germline MYH Mutations Research Articles

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations.

Patients with multiple colorectal adenomas (MCRA) without genetic cause are increasingly being diagnosed. The characteristics and natural history of this condition are not well studied. Twenty-seven patients with MCRA, with cumulatively 10 to 99 colorectal adenomas and without deleterious mutations of APC or MYH genes, were investigated. Results of colonoscopies with a mean follow-up of 4.9 years (range, 0 to 27 y) were evaluated. Findings from esophagogastroduodenoscopy and extracolonic manifestations were assessed. The mean age at polyp diagnosis and MCRA diagnosis was 47.8±13.1 years (range, 21 to 72 y) and 50.4±14.6 years (range, 21 to 72 y), respectively. In 22% of patients another family member had MCRA. At first colonoscopy, the mean number of adenomas was 35.0±35.9 (range, 0 to 99). Serrated polyps were rare. Esophagogastroduodenoscopy revealed 47% of patients had upper tract neoplasia. Patients with upper tract findings were diagnosed with MCRA at significantly younger mean age than those without findings, P<0.05. Eighteen patients (67%) underwent colectomy with a mean time from diagnosis of MCRA of 3.1±1.3 years. After surgery, surveyed patients developed recurrent adenomas in retained colorectum. Nine patients (33%) had extracolonic cancers. MCRA patients have a similar clinicopathologic phenotype to known syndromes of attenuated adenomatous polyposis and the majority have need for colectomy. The management of MCRA patients and families should parallel that of attenuated familial adenomatous polyposis and MUTYH-associated polyposis including surveillance of the upper tract.

Multiple Adenomatous Duodenal Polyposis

Multiple duodenal polyps are a relatively rare finding, usually co-occurrent with familial adenomatous polyposis (FAP).We report a patient with multiple duodenal adenomas and a negative examination for FAP: multiple flat polyps were detected endoscopically in a 37-year-old male patient, extending from the apex of the bulb to the end of the descending part of the duodenum. In terms of histology, they were tubular adenomas with moderate dysplasia. Colonoscopy and enteroclysis were normal. Both push and capsule enteroscopy only showed multiple polyps in the area of the descending duodenum. DNA analysis of the APC gene was as follows: DGGE, exon 1–15, deletion at codons 1309 and 1061 by means of PCR for attenuated APC were negative. Afterwards we screened the patient for germline MYH mutations using the denaturing high-performance liquid chromatography (DHPLC) in combination with sequencing. No novel pathogenic mutation has been identified. Large polyps were removed by means of endoscopic polypectomy and mucosectomy, while small polyps were removed by means of argon plasma coagulation.We conduct yearly checkups, removing only sporadic polyps. The rare finding of duodenal polyposis not co-occurrent with FAP proves that multiple adenomas in the digestive tube need not necessarily co-occur with FAP.

The first mutations in the MYH gene reported in Moroccan colon cancer patients

BackgroundBiallelic germline mutations in the MYH gene cause MYH-associated polyposis (MAP) disease, an autosomal recessive form of inherited colorectal cancer. People with MAP tend to develop attenuated multiple adenomatous colon polyps during their lifetime and will have an increased risk of colorectal cancer. Contrary to familial adenomatous polyposis, the number of adenomas is often lower in MAP (from 5 to 100), and even some patients have recently been reported with no identified adenomas.There have been many investigations into MAP that have been conducted in many different countries. Currently there is limited data on MAP in Morocco, and it is reasonable to think, that the prevalence of this form of genetic predisposition is as high as other autosomal recessive genetic diseases found in countries with high rates of consanguinity.The aim of this study is to examine the frequency of MYH mutations in colorectal cancer and/or attenuated polyposis in Moroccan patients. Patients and methodsThe study population consisted of 62 patients; 52 with colorectal cancer, three of them had attenuated polyposis (2 to 99 adenomatous polyps). 10 other patients were referred to our department for polyposis without colorectal cancer.We carried out DNA analysis in 62 patients to screen for the three recurrent mutations c.494A>G (p.Tyr165Cys), c.1145G>A (p.Gly382Asp) and c.1185_1186dup, p.Glu396GlyfsX43, whereas 40 subjects were screened for germline MYH mutations in the whole coding sequence of the MYH gene by direct DNA sequencing. All these 40 patients, except two, had colorectal cancer without polyposis. ResultsThree patients with colorectal cancer and attenuated polyposis carried biallelic mutations in the MUTYH gene one with the c.494 A>G mutation, one with the c.1105delC mutation, one with the c.1145G>A mutation. One patient with 25 adenomas without colorectal cancer carried the c.1145G>A mutation at a homozygote state and one patient with 3 polyps was heterozygote for the mutation c.1145G>A. No biallelic mutations of MYH gene were detected in colorectal cancer patients and in patients with small number (<5) of polyps without colorectal cancer. ConclusionWe report the first biallelic MYH mutations in four Moroccan patients with clinical criteria of MAP; three of them had colorectal cancer with attenuated polyposis. No MYH mutations were found in colorectal patients without polyposis.Despite the relatively small sample size of the current study, our findings suggest that the MAP is not a frequent cause of colon cancer in Morocco as we had expected, and the molecular analysis of MYH gene should be restricted to patients displaying the classical phenotype of MAP.

Aggressive Phenotype of MYH-Associated Polyposis with Jejunal Cancer and Intra-Abdominal Desmoid Tumor

MYH-associated polyposis is an inherited autosomal recessive disease, linked to biallelic germline MYH mutations, which predisposes to the development of multiple colorectal adenomas and cancer. The colonic and extracolonic phenotype of this syndrome is very heterogeneous. We report the case of a young male patient with an aggressive MYH-associated polyposis phenotype. He presented at aged 30 years with more than 100 colonic polyps and 4 colonic adenocarcinomas. At aged 35 years, Spigelman Stage IV duodenal adenomatosis was detected. When he was 39 years old, he developed three synchronous jejunal adenocarcinomas and a mesenteric desmoid tumor. Based on this report, we believe that screening of the entire small bowel should be recommended in MYH-associated polyposis patients, especially in those with duodenal adenomas. Similar to patients with familial adenomatous polyposis, desmoid tumors also may be part of the clinical spectrum of MYH-associated polyposis and may prove to be a significant clinical problem in patients submitted to prophylactic colectomy.

Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient

The incidence of several extracolonic tumors, such as duodenal carcinoma, is higher in familial adenomatous polyposis (FAP) patients than in the general population, but there is little information about lung carcinoma in FAP. A 43-year-old woman presented with a lung tumor 17 years after total colectomy for FAP. Pathohistological analysis of the lung tumor demonstrated mixed adenocarcinoma consisting of a papillary adenocarcinoma component and a bronchioloalveolar carcinoma component. Sequencing analysis indicated a germline APC mutation from TCA to TGA (stop) at codon 1110, but no pathogenic germline MYH mutations. The other APC allele in the lung carcinoma was not inactivated by somatic mutations, promoter methylation, or chromosomal deletion. No somatic mutations in any of the coding regions of the p53 gene or in the mutation hot spot regions of the K-ras or EGFR genes were detected in the carcinoma. Amplification, however, of three chromosome regions, 5p, 8q, and 12q14-12q21, was identified in the carcinoma on genome-wide high-resolution single-nucleotide polymorphism (SNP) microarray. The present results suggest that the chromosomal copy number alterations detected on SNP microarray were involved in the carcinogenesis of the adenocarcinoma of the lung in the present FAP patient.

Characterization of Mutant MUTYH Proteins Associated With Familial Colorectal Cancer

The human mutyh gene encodes a base excision repair protein that prevents G:C to T:A transversions in DNA. Biallelic mutations in this gene are associated with recessively inherited familial colorectal cancer. The aim of this study was to characterize the functional activity of mutant-MUTYH and single-nucleotide polymorphism (SNP)-MUTYH proteins involving familial colorectal cancer. MUTYH variants were cloned and assayed for their glycosylase and DNA binding activities using synthetic double-stranded oligonucleotide substrates by analyzing cleavage products by polyacrylamide gel electrophoresis. In this study, we have characterized 9 missense/frameshift mutants and 2 SNPs for their DNA binding and repair activity in vitro. Two missense mutants (R260Q and G382D) were found to be partially active in both glycosylase and DNA binding, whereas 3 other missense mutants (Y165C, R231H, and P281L) were severely defective in both activities. All of the frameshift mutants (Y90X, Q377X, E466X, and 1103delC) were completely devoid of both glycosylase and DNA binding activities. One SNP (V22M) showed the same activity as wild-type MUTYH protein, but the other SNP (Q324H) was partially impaired in adenine removal. This study of MUTYH mutants suggests that certain SNPs may be as partially dysfunctional in base excision repair as missense-MUTYH mutants and lead to colorectal carcinogenesis.

BRAF Mutations in Multiple Sebaceous Hyperplasias of Patients Belonging to MYH-Associated Polyposis Pedigrees

The characteristics of sebaceous gland hyperplasia (SGH) consist of yellowish or skin-colored papules and nodules. Chronic sun exposure and immunosuppressed conditions are the main environmental risk factors, whereas chronological aging regulated by hormones and molecular changes are the intrinsic risk factors. We have evaluated the contribution of BRAF, K-Ras, and N-Ras mutations to the pathogenesis of SGHs in four patients belonging to three MYH-associated polyposis (MAP) pedigrees. MAP is an autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. Immunohistochemistry of mismatch repair and APC proteins was performed. DNA isolated from blood lymphocytes and formalin-fixed or paraffin-embedded SGHs was PCR amplified and sequenced. In the SGH patients, we detected T1796A heterozygous substitution (V600E) in the BRAF gene. Compound biallelic germline MYH mutations (Y165C/G382D, R168H/379delC, and Y90X/delGGA464) were detected in the MAP patients. In contrast to the majority of melanocytic lesions, activating hotspot mutations in BRAF have not been involved so far in the pathogenesis of SGH. BRAF mutation is not a specific marker of melanocytic cancerogenesis, and it can also be involved in SGHs. In both melanocytic and non-melanocytic skin tumors, BRAF mutation is linked to early tumorigenesis events.

Mutation analysis of the MYH gene in unrelated Czech APC mutation-negative polyposis patients

Some of the APC negative FAP and AFAP cases have recently been found to be attributable to MYH associated polyposis (MAP). MAP is an autosomal recessive syndrome associated with 5–100 colorectal adenomas and caused by mutation in the MYH gene. Here, we screened for germline MYH mutations in 82 APC-mutation-negative probands with classical and attenuated familial adenomatous polyposis using the denaturing high performance liquid chromatography (DHPLC) method in combination with sequencing. Altogether 12 previously reported changes and four novel genetic alterations, mostly in intronic sequences, were identified. The results revealed the presence of biallelic germline MYH mutations in two patients. These patients were compound heterozygotes for two of the most common germline mutations c.494 A > G (p.Y165C); c.1145 G > A (p.G382D). These variants are established to be associated with adenomatous polyposis and colorectal cancer. No novel pathogenic mutation has been identified in our study.

MYH mutations are rare in prostate cancer

Oxidative stress is considered a risk factor for prostate cancer development and is associated with the production of reactive oxygen species (ROS). The base excision repair gene MYH protects against ROS-mediated damage to DNA. Inherited MYH mutations predispose to colorectal adenomas and cancer. A compromised base-excision repair function due to defective MYH may contribute to prostate carcinogenesis. Here, we examine the genetic contribution of MYH to prostate cancer risk. Patients diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) alone (n = 45), prostate cancer alone (n = 123) or both (n = 82) were screened for the two most common mutations in the MYH gene using PCR-based RFLP analysis. A single patient with an inherited MYH mutation as well as a subset of 26 patients presenting with a family history of colorectal cancer were screened for additional MYH mutations by direct sequencing of the entire coding region. Biallelic germline mutations in MYH were not detected among prostate cancer patients. Only a single patient was a heterozygous carrier for the Y165C missense mutation. Allelic deletion or somatic mutation of the remaining MYH allele was not identified in this patient's tumor DNA. Two patients harbored V22M polymorphism and three patients were carriers of Q324H polymorphism. MYH mutations are unlikely to contribute to prostate cancer risk.

Germline MYH mutations in a clinic‐based series of Canadian multiple colorectal adenoma patients

MYH is a member of the DNA base excision repair (BER) pathway and mutations of this gene predispose to the development of colorectal neoplasia in an autosomal recessive transmission pattern. Our objective was to determine the significance of MYH mutations in a series of Canadian patients with multiple adenomas. We screened for germline MYH mutations (by dHPLCO) in 20 clinic-based multiple adenoma patients who were adenomatous polyposis coli (APC) mutation-negative. Suspected mutations were confirmed by sequence analysis. Six of 20 (30%) patients carried pathogenic biallelic MYH mutations, 1 Y165C homozygote and 5 compound heterozygotes of other sequence variants. We identified three novel variants, Q377X, 1314delA, and P281L, which are likely pathogenic. Twenty-nine relatives of the Y90X/1103delC compound heterozygous carrier were also screened for germline MYH mutations, and 1 homozygous and 14 heterozygous carriers were identified. Among patients with multiple adenomas, biallelic MYH mutations account for approximately 30% of APC mutation negative cases and two thirds of these carry mutations other than the "common" Y165C and G382D variants. Clinical screening algorithms which focus only on the Y165C and G382D alleles are inadequate since additional pathogenic mutations may be identified by screening the entire gene.

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Immunohistochemical Expression of MYH Protein Can Be Used to Identify Patients With MYH-Associated Polyposis

MYH-associated polyposis is a recently described, autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. There are only few immunohistochemical studies of the MYH protein. We investigated the expression pattern of the MYH protein to evaluate whether a immunohistochemical approach could be used in clinical practice to screen patients for germline mutations in the MYH gene. The expression of MYH, MSH2, MLH1, and MSH6 proteins was studied by immunohistochemistry in 20 samples (colorectal adenomas or cancer) from 18 patients with biallelic MYH mutation, in 11 samples from patients with germline adenomatous polyposis coli (APC) mutations, in 20 samples from patients with sporadic colorectal cancers, and in 10 samples from patients with normal colonic mucosa without malignancies. In all cases the mismatch repair proteins were expressed normally. Nuclear and cytoplasmic immunoreactivity for the MYH protein were observed in normal colorectal mucosa, in sporadic colorectal carcinomas, and in adenomas and carcinomas from patients carrying APC germline mutations. Adenomas and carcinomas from patients with MYH biallelic mutation showed a different pattern of expression: a strong granular cytoplasmic staining was observed without any nuclear expression. The same immunophenotype was observed in the surrounding normal mucosa. Patients with biallelic MYH mutations showed disappearance of staining from the nucleus, and segregation of immunoreactivity in the cytoplasm, both in neoplastic and surrounding healthy mucosa. Because this pattern of expression seems to be specific for biallelic mutations, it follows that immunohistochemistry might be used in clinical practice to screen patients at risk for MYH-associated polyposis.

Microsatellite Stable Colorectal Cancers in Clinically Suspected Hereditary Nonpolyposis Colorectal Cancer Patients without Vertical Transmission of Disease Are Unlikely to Be Caused by Biallelic Germline Mutations in MYH

Microsatellite analysis and immunohistochemistry are commonly used initial screening tests for hereditary nonpolyposis colorectal cancer. However, tumors in roughly one-half of the patients fulfilling the Bethesda guidelines are microsatellite stable. In addition, normal mismatch repair protein expression in these tumors suggests that a defect in the mismatch repair system is unlikely. Because biallelic MYH mutations occur in patients with both high and low numbers of adenomas, we hypothesized that MYH is involved in the tumorigenesis of microsatellite stable colorectal cancers in patients without vertical transmission of disease and who fulfill the Bethesda guidelines. MYH was analyzed in 50 cancer patients and 116 healthy controls by complete genomic DNA sequencing. No biallelic germline mutations were identified. One patient was a heterozygous carrier for the p.G382D missense mutation, and another patient was a heterozygous carrier for the novel missense mutation p.Q484H. We identified six common variants, three in the coding region (p.V22M, p.Q324H, and p.S501F) and three in adjacent intronic regions (c.157+30A>G, c.462+35G>A, and c.1435-40G>C). In summary, biallelic germline mutations of MYH are unlikely to cause colorectal cancer in patients sharing clinical features with hereditary nonpolyposis colorectal cancer families without mismatch repair defect and therefore cannot fill the molecular diagnostic gap in this subgroup of Bethesda-positive patients.

MYH Y165C and G382D mutations in hepatocellular carcinoma and cholangiocarcinoma patients

Production of reactive oxygen species (ROS) during chronic inflammation has been implicated in the progression of liver diseases and carcinogenesis. Subjects with inflammatory liver disease and one non-functional allele of the base excision repair gene, MYH, may be more susceptible to progression to cancer due to MYH haploinsufficiency in repairing oxidative damage caused by ROS. Here, we investigated the association of two common germline MYH mutations in patients with hepatocellular carcinoma (HCC) and cholangiocarcinoma. DNA from patients with HCC (n=48) or cholangiocarcinoma (n=84) compared to non-cancerous controls (n=308) were genotyped for the Y165C and G382D mutations in MYH. There was no significant difference in MYH mutation carrier status between patients with HCC (1/48), cholangiocarcinoma (3/84), and non-cancerous controls (4/308). Patients with HCC or cholangiocarcinoma do not have an increased incidence of monoallelic MYH mutations pre-disposing them to disease.

Prevalence of MYH germline mutations in Swiss APC mutation‐negative polyposis patients

In 10-30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli (APC) gene can be identified (APC mutation-negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to (i) assess the MYH mutation carrier frequency among Swiss APC mutation-negative patients and (ii) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation-negative polyposis patients. Seventy-nine unrelated APC mutation-negative Swiss patients with either classical (n=18) or attenuated (n=61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance (n=45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly (p<0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation-negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: (i) presence of classical or attenuated polyposis coli, (ii) absence of a pathogenic APC mutation, and (iii) a family history compatible with an autosomal recessive mode of inheritance.

Correlation of Polyp Number and Family History of Colon Cancer With Germline MYH Mutations

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. 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. 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. 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.

Is prophylactic colectomy indicated in patients with MYH‐associated polyposis?

The MYH gene has recently been associated with multiple colorectal tumours. It participates in the DNA base-excision-repair, avoiding mutations in other genes, namely the APC and Ki-ras. Recently, biallelic MYH mutations have been described in patients with attenuated polyposis and in 7.5% with classic polyposis and no detectable APC mutation. The aim of this study was to analyse the incidence of germ-line MYH mutations in selected Portuguese families recorded in a hereditary tumour registry and to evaluate the risk of colorectal cancer in this syndrome. Nineteen APC mutation negative patients, 13 presenting attenuated polyposis and 6 with classic familial adenomatous polyposis (> 100 adenomas), were screened for germline biallelic MYH mutations. Biallelic germline mutations in MYH were identified in 9 of the attenuated polyposis and in one of the classic polyposis patients. The mean age at the clinical diagnosis was 50.6 years (from 35 to 69 years); six were men and four women. Five patients belonged to families with affected siblings; three showed evidence for vertical transmission and two had no evidence for familial transmission of the disease. No extra-colonic manifestations were reported. All patients had surgical resections: five total colectomies, four reconstructive proctocolectomies and one left hemicolectomy. Eight patients had associated malignant degeneration: three T3N+, four T3N0 and one T1N+. In the follow-up two patients died due to tumour recurrence. A large frequency of biallelic MYH mutations (69%) was found in APC mutation negative patients belonging to families with attenuated polyposis; the highest percentage was observed in families presenting evidence for horizontal transmission of the disease. The high percentage of degeneration found in these patients suggests that colonoscopy with polypectomies is not sufficient and prophylactic colectomy is recommended. The identification of MYH associated polyposis is important to evaluate the level of risk, particularly for the siblings.

476 Germline MYH mutations and risk of colorectal cancer

476 Germline MYH mutations and risk of colorectal cancer

MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps

Background & Aims: MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis have biallelic mutations in MYH, a base excision repair gene, and are negative for germline mutations in the APC gene. In this study, the 2 most prevalent MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0–3 polyps, 444 with colorectal cancer (CRC), and 140 referred for APC mutation analysis in which a germline mutation was not identified. Methods: Genotyping for Y165C and G382D was performed by Pyrosequencing. Results: Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0–3 polyps (n = 400), in those APC-negative patients with <20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2 MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline MYH mutations correlated with the presence of ≥20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in MYH. Conclusions: These data suggest that screening of MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.

Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas.

Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer. In contrast to the classic dominant condition of familial adenomatous polyposis (FAP) due to germinal mutations in the APC gene, the MYH polyposis is an autosomal recessive disease. The identification of individuals affected by MYH polyposis brings new and important implications for the diagnostic, screening, genetic counseling, follow up and therapeutic options in these patients. In this study, screening for germinal mutations in the MYH gene was performed in 53 Portuguese individuals with multiple colorectal adenomas or classic adenomatous polyposis, in whom no mutation had been identified in the APC gene. The results revealed the presence of biallelic germline MYH mutations in 21 patients. In addition, we here report 3 mutations (c.340T>C [p.Y114H]; c.503G>A [p.R168H]; and c.1186_1187insGG [p.E396fsX437]) which, to our knowledge, have not been previously described.