MLH1constitutional and somatic methylation in patients with MLH1 negative tumors fulfilling the revised Bethesda criteria

Purpose Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6. Patients and Methods Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients. Results Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4. Conclusion Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.

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Characterization of family history profiles in a large series of Lynch syndrome carriers.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.414 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 414-414

Author(s):

Devki Saraiya ◽

Sara J. Wiyrick ◽

Barry S. Tong ◽

Kelsey Moyes ◽

Elizabeth Garner

Keyword(s):

Genetic Testing ◽

Family History ◽

Lynch Syndrome ◽

Single Gene ◽

Healthcare Providers ◽

Degree Relative ◽

Large Rearrangement ◽

Full Sequence ◽

Bethesda Criteria ◽

Second Degree

414 Background: The identification of Lynch syndrome carriers is an unmet medical need. Large studies characterizing family history profiles of unaffected individuals diagnosed with Lynch syndrome in the absence of a known family mutation have not been reported. Methods: We queried our laboratory database for unaffected patients who underwent Lynch syndrome genetic testing between September 2010 and May 2013 and had a positive test result. All individuals underwent full sequence and large rearrangement analysis of MLH1 and MSH2, and full sequence analysis of MSH6. Some patients also underwent full sequence and large rearrangement analysis of PMS2 and large rearrangement analysis of MSH6 and EPCAM. Those being tested for a known mutation in the family and patients undergoing single gene testing were excluded. We assessed family history profiles in 200 unaffected patients with genetically confirmed Lynch syndrome. Results: Of the 200 patients, 162 female and 38 male Lynch syndrome carriers were identified. Mutations in MLH1 and MSH2 were the most common (30.0% and 32.5%) while mutations in MSH6, PMS2, and EPCAM accounted for 21.0%, 13.5%, and 3.0% of all deleterious mutations, respectively. Eighteen patients did not have a first or second degree relative with colorectal cancer. Only 37.8% (73/193) of individuals had a first- or second-degree relative meeting the Amsterdam II criteria and 76.8 % (149/194) of individuals had a first or second degree relative meeting the Revised Bethesda criteria. The average PREMM1,2,6 score was 10.0% with 43.5% (87/200) falling below 5%. In this large cohort, 15.5% (31/200) had neither a first or second degree relative who met the Amsterdam II or Revised Bethesda criteria nor a PREMM1,2,6 score of 5% or greater. Conclusions: In order to improve detection of Lynch syndrome in the population, it is important to consider genetic testing in unaffected individuals even in the absence of a known family mutation. Development of guidelines that include having a single affected relative and extra-colonic cancers is needed to support healthcare providers in identifying appropriate patients for testing.

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Diagnostic value of bethesda criteria for HNPCC-screening

Gastroenterology ◽

10.1016/s0016-5085(98)82576-6 ◽

1998 ◽

Vol 114 ◽

pp. A630-A631

Author(s):

F. Kullmann ◽

A. Beham ◽

W. Dietmaier ◽

T. Bocker ◽

V.D. Mohr ◽

...

Keyword(s):

Diagnostic Value ◽

Bethesda Criteria

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Screening and genetic counseling practices for hereditary non-polyposis colorectal cancer (HNPCC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6564 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6564-6564

Author(s):

S. Karri ◽

S. R. Govindarajan ◽

W. B. Bendure ◽

S. A. Jackson ◽

K. D. McKelvey ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Counseling ◽

Health Care Providers ◽

Medical Center ◽

University Of Arkansas ◽

Care Providers ◽

Medical Sciences ◽

Bethesda Criteria ◽

Autosomal Dominant Fashion ◽

The University

6564 Background: HNPCC, the most common cause of hereditary colorectal cancer (CRC), is inherited in an autosomal dominant fashion and caused by micro satellite instability and mutations in mismatch repair genes. Affected patients (pts) and first degree relatives tend to develop colonic and extra colonic tumors that need to be tested for the mutations. Genetic consultation (GC) should be routinely offered to the affected pts and relatives. To assess the utilization of GC, we assessed the frequency of referral for GC for the presence of HNPCC syndrome at our medical center. Methods: Patients with CRC were identified from the tumor registry at the University of Arkansas for Medical Sciences (UAMS) and the Central Arkansas Veterans Healthcare System (CAVHS) from January 1st 2000 to September, 2006. Pts’ charts were reviewed for synchronous or metachronous HNPCC tumors and family history (FH). FH was categorized as positive according to the Bethesda criteria (BC, 2000–2002), revised Bethesda criteria (RBC, 2003–2006), negative (documented FH but no h/o cancer) or inadequate documentation. Percentage of pts with positive FH for HNPCC syndrome and those with CRC less than 50 years of age (for pts diagnosed 2003–2006) who were referred for GC was calculated. The list of these pts was cross referenced to the list in genetics clinic at UAMS and CAVHS. Results: 858 patient charts were reviewed. Table 1 shows the number of pts meeting criteria for genetic counseling. 138 (16%) pts had inadequate /no documented FH. Of the 720 pts with documented FH, 67 (9.3%) had positive FH and 126(17%) met BC / RBC. Only 13 (10.3%) of 126 pts were referred for genetic counseling. The number of pts eligible for GC increased with inclusion of RBC. However, the percentage of eligible pts referred for GC was extremely low. Conclusions: FH is not adequately documented in many pts presenting with CRC. Only a small percentage of pts who qualify for GC are referred. Education of health care providers for referral to genetics counseling is warranted. No significant financial relationships to disclose. [Table: see text]

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