Clustering Of Colorectal Cancer Research Articles

Lynch syndrome diagnostics: decision-making process for germ-line testing

Cancer risks and medical management of Lynch syndrome (LS) differ from other hereditary or familial clustering of colorectal cancer. Differential diagnosis has improved as a result of the growing clinical and molecular knowledge about LS. Appropriate application of these advances in several scenarios constitutes a decision-making process to further decide germ-line testing with accuracy and efficiency. However, an only molecular-screening algorithm, with a limited number of steps and choices, may be difficult to devise. How, when, where and at what expense to use the different diagnostic tools remain dynamic and changeable under different circumstances. From a clinical point of view, it is advisable to discuss conflicting aspects to guide LS diagnosis.

Increased frequency of disease-causing MYH mutations in colon cancer families

The genetic factors that cause clustering of colorectal cancers (CRCs) other than mutations in the mismatch repair (MMR) genes are not well understood. Clustering in families who lack MMR gene mutations may be attributable to low-penetrance mutations. Hypothetically, mono-allelic MYH mutations could contribute to the risk of CRC in these families. Using Fisher's exact test and logistic regression, we compared the frequency of the known disease-causing MYH mutations Y165C, G382D and 466delE in 137 probands (117 cases with CRC and 20 cases diagnosed on the basis of adenomatous polyps only) from families with three or more CRCs but negative for mutations in the MMR genes and in 967 healthy controls with comparable ethnic backgrounds. Of 137 cases, 6 (4.4%) carried mono-allelic MYH mutations compared with 16 of 967 (1.6%) controls. In addition, three bi-allelic MYH mutation carriers, who eventually developed MYH-associated polyposis, were also identified in families with pedigree structures consistent with dominant inheritance of CRC susceptibility. By Fisher's exact tests, there was a statistically different frequency of cases with any MYH mutation (mono- or bi-allelic carriers; P-value = 0.002) and of cases with mono-allelic MYH mutation (P = 0.04) compared with the controls. Using a logistic regression model, the unadjusted odds ratio associated with any MYH mutation was 4.14 (P-value < 0.001); for mono-allelic carriers, it was 2.79 (P-value = 0.04). Adjusting for ethnic backgrounds, gender and age, the odds ratio associated with any disease-causing MYH mutation was 3.23 (P-value = 0.01); for mono-allelic carriers, it was 1.99 (P-value = 0.20). Overall, the results support previous studies suggesting that mono-allelic mutations of MYH constitute low-penetrance CRC-causing alleles. These data further support a model in which low-penetrance alleles are enriched in MMR gene mutation-negative CRC families.

Immunohistochemical expression (IHC) and microsatellite instability (MSI) analysis in families with clustering of colorectal cancer

Immunohistochemical expression (IHC) and microsatellite instability (MSI) analysis in families with clustering of colorectal cancer

Analysis of Mismatch Repair Defects in the Familial Occurrence of Lymphoma and Colorectal Cancer

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant disorder featuring familial clustering of colorectal and/or endometrial cancer, and other malignancies. Except for a rare case report, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) have not been considered part of HNPCC. Recent murine models for HNPCC have shown an increased incidence of B- and T-cell lymphoma, as well as tumors of the gastrointestinal tract and other organ systems, involving defects in genes resulting in faulty mismatch repair (MMR) of DNA. These MMR genes include MLH 1, MSH 2, MSH 3, MSH 6, PMS 1 and PMS 2. We sought to analyze the occurrence of NHL and HD in families with clusters of colorectal cancers (CRC). Probands from 21 kindreds were classified as HNPCC (3), HNPCC-like (5), and HNPCC-variant (13); seen and followed by Clinical Genetics at Memorial Hospital the kindreds were assessed for the occurrence of NHL or HD. Of the 21 pedigrees, a total of 37 patients were identified who were diagnosed with leukemia, lymphoma, or HD. Fourteen of the 37 patients with a diagnosis of NHL or HD were further classified and showed varying histologies ranging from chronic lymphocytic leukemia/small lymphocytic lymphoma (2), mycosis fungoides (1), follicular lymphoma (1), extranodal marginal zone lymphoma of MALT type (2), diffuse large B-cell lymphoma (4), nodular sclerosis HD (3), and mixed cellularity HD (1). Microsatellite instability studies were performed on 6 cases but none showed evidence of replication error repair defects. Immunohistochemical stains performed on paraffin sections from these 6 representative cases showed differential protein expression of MLH1, MSH2, MSH6, and PMS2 when compared to normal reactive tissues from the same patient but showed no significant differences when compared to controls of non-familial, sporadic lymphomas. These results suggest that lymphomas arising in the setting of familial CRC do not bear the molecular hallmarks of HNPCC. Further studies are needed to explain the differential patterns of expression of RER-associated proteins in lymphomas, as well as the association of lymphomas and possibly renal cell cancers in a subset of kindreds in which CRC clustering is evident.

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.

Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1. Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

Clustering of colorectal cancer in families of probands under 40 years of age.

Although sporadic colorectal cancer (CRC) is relatively uncommon in the young, it may constitute an elevated genetic risk for CRC in these individuals. This study was designed to determine extent of colorectal cancer in families of probands under 40 years of age. Medical records of all consecutive patients, 40 years of age or younger at the time of CRC surgery, during the time period 1986 to 1994 were examined. Cases of familial adenomatous polyposis and ulcerative colitis were excluded. Via interviews of surviving probands or nearest relatives, dates of birth and death, causes of death, and diagnosis of cancer were recorded on all first-degree relatives (parents, siblings, and offspring), second-degree relatives (grandparents, aunts, and uncles), and any other relatives. A total of 128 patients, 40 years of age or less at time of CRC resection, were identified. Of these, 45 probands/families were reached by phone, and 45 detailed family histories were obtained. Age range of these 45 probands was 19 to 40 (mean, 33.1) years. In 25 families there was no history of CRC in first-degree, second-degree, or third-degree relatives. Eight of 45 probands (17.8 percent) had at least one first-degree relative with CRC, and three of these eight families fulfilled the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC). In all three families, inheritance of CRC appeared to segregate with the maternal side of the family. In addition, 5 of 43 non-HNPCC probands had at least one first-degree, second-degree, or third-degree relative less than 40 years of age, at time of CRC diagnosis. Ascertainment of a detailed family history in early age of onset CRC patients identifies frequent familial clustering of CRC and HNPCC in 17.8 percent of cases.

Excess familial clustering of colorectal cancer: Clinical and epidemiological identification of hereditary colorectal cancer

Excess familial clustering of colorectal cancer: Clinical and epidemiological identification of hereditary colorectal cancer