Recommendations for the Care of Individuals With an Inherited Predisposition to Lynch Syndrome

Lindor, Noralane M.; Petersen, Gloria M.; Hadley, Donald W.; Kinney, Anita Y.; Miesfeldt, Susan; Lu, Karen H.; Lynch, Patrick J.; Burke, Wylie; Press, Nancy

doi:10.1001/jama.296.12.1507

Cited by 595 publications

(530 citation statements)

References 100 publications

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“…Whether women from HBOS families exhibiting PC should seek early oophorectomy or aggressive ovarian screening is unknown. Both ovarian and PC risks are also increased in HNPCC/Lynch syndrome, but no coupling of these risks has been reported to date (Aarnio et al 1999;Lindor et al 2005). In efforts to further explore this question, our group has recently identified a significant association between ovarian cancer (first primary malignancy) and PC (second primary malignancy) using the SEER registry (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

Hall

Dignam²,

Olopade

2008

Journal of Genetic Counseling

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Detailed family history is a critical element of cancer risk assessment. The relative importance of pancreatic cancer (PC) in a close family member, particularly in hereditary breast-ovarian syndrome (HBOS), is not clearly defined. We use a case-control design to investigate the importance of a family history of PC to cancer risk assessment. Case and control families were identified from the University of Chicago Cancer Risk database (1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005). Pedigrees were analyzed for personal and familial clinical cancer data. Cases included all new subjects (probands) reporting a close relative (first or second degree) with PC. Controls included the probands enrolled in the database immediately prior to and subsequent to each case (i.e. two controls for each case). From 1,231 pedigrees, 103 PC were reported by the proband in 87 unique families. Many probands reported multiple or early-onset PCs: one third (28/87) of case families met criteria for a familial PC syndrome [≥2 first-degree relatives with PC (n=10) or PC diagnosed ≤50 (n=18)]. Of these families, the majority (75%) concurrently met criteria suggestive of hereditary breastovarian syndrome (HBOS). Because of a family history consistent with HBOS, at least one individual from each of 29 case and 55 control families underwent genetic testing for BRCA1/2. Among case families, 19 of 29 (66%) had a BRCA1/2 mutation compared with 16 of 55 (29%) controls. A significant association between family history of PC and a BRCA1/2 mutation was seen (OR 3.78,). This point estimate was strengthened but less precise in the nonAshkenazi Jewish subset of tested families (OR 6.03,. In a high-risk population, a family history of PC, though infrequently reported, is nonetheless clinically meaningful. In risk assessment for HBOS, identifying a family history of PC should strongly raise the suspicion of an unrecognized BRCA1/2 mutation.

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Section: Discussionmentioning

confidence: 99%

Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

Hall

Dignam²,

Olopade

2008

Journal of Genetic Counseling

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“…Recommendations for those families with known or highly suspected Lynch syndrome are as follows (23). Colonoscopy is generally offered every 1-2 years starting at the age of 20 to 25 years or 10 years younger than the youngest age at diagnosis in the family.…”

Section: Discussionmentioning

confidence: 99%

“…Clear recommendations for genetic counseling, increased cancer surveillance and prevention in these families that fulfill Amsterdam criteria yet lack mutations in DMMR is unknown and demands further exploration. Professional organizations such as the American Cancer Society recommends colonoscopy every 5-10 years in these high risk families where colorectal cancer or polyps have been diagnosed prior to age 60 in any first-degree relative or in 2 or more first-degree relatives at any age (23). Although the molecular mechanism or specific gene contributing to the cancer phenotype is unknown, penetrance is high and these patients do warrant some form of increased surveillance; historically clinical judgement has been utilized to determine if Lynch syndrome screening guidelines are appropriate based on the cancer profile of the family.…”

Section: Discussionmentioning

confidence: 99%

“…Sutter et al screened 94 individuals with a high index of suspicion for genetic disease for MLH1 epimutation in PBLs. They found only two such examples which proved to be germline epimutations in both cases (23). Germline epimutation in individual III-4 is unlikely based on the lack of MLH1 methylation in other tissues (hair, bladder epithelium, buccal cells).…”

Section: Discussionmentioning

confidence: 99%

“…Extra-colonic malignancies are especially prevalent in women with Lynch syndrome as they have a higher risk of endometrial cancer than CRC (7). The identification of Lynch syndrome families is of paramount importance as these individuals may benefit from genetic counseling, genetic testing, and more intense cancer surveillance (8).…”

Section: Introductionmentioning

confidence: 99%

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Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Case

Zighelboim

Mutch

et al. 2008

Gynecologic Oncology

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Objectives-We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication.Methods-A detailed history and review of medical records was undertaken to construct a fourgeneration pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation.Results-Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer.Conclusions-We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

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Cancer Risks Associated With Germline Mutations in <emph type="ital">MLH1</emph>, <emph type="ital">MSH2</emph>, and <emph type="ital">MSH6</emph> Genes in Lynch Syndrome

Bonadona¹

2011

JAMA

947

580

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Recommendations for the Care of Individuals With an Inherited Predisposition to Lynch Syndrome

Cited by 595 publications

References 100 publications

Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Cancer Risks Associated With Germline Mutations in <emph type="ital">MLH1</emph>, <emph type="ital">MSH2</emph>, and <emph type="ital">MSH6</emph> Genes in Lynch Syndrome

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