Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management

Abstract

Hereditary forms of colorectal cancer, as is the case with virtually all forms of hereditary cancer, show extensive phenotypic and genotypic heterogeneity, a phenomenon discussed throughout this special issue of Familial Cancer. Clearly, the family physician, oncology specialist, genetic counselor, and cancer geneticist must know fully the complexity of hereditary cancer syndromes, their differential diagnosis, in order to establish a diagnosis, direct highly-targeted surveillance and management, and then be able to communicate effectively with the molecular geneticist so that an at-risk patient's DNA can be tested in accord with the syndrome of concern. Thus, a family with features of the Lynch syndrome will merit microsatellite instability testing, consideration for immunohistochemistry evaluation, and mismatch repair gene testing, while, in contrast, a patient with FAP will require APC testing. However, other germline mutations, yet to be identified, may be important should testing for these mutations prove to be absent and, therein, unrewarding to the patient. Nevertheless, our position is that if the patient's family history is consistent with one of these syndromes, but a mutation is not found in the family, we still recommend the same surveillance and management strategies for patients from families with an established cancer-causing germline mutation. Our purpose in this paper is to provide a concise coverage of the major hereditary colorectal cancer syndromes, to discuss genetic counseling, molecular genetic evaluation, highly targeted surveillance and management, so that cancer control can be maximized for these high hereditary cancer risk patients.

Breast cancer susceptibility: current knowledge and implications for genetic counselling

“…175200) carrying heterozygous germline mutations in STK11, formerly known as LKB1, causing a polyposis syndrome characterized by melanocytic macules of the lips, buccal mucosa and digits as well as multiple gastrointestinal hamartomatous polyps and an increased risk of various neoplasms, including breast cancer. 19 For age-dependent screening procedures, please see the recent review by Lynch et al 22 Cowden syndrome (MIM no. 158350), characterized by multiple hamartomas occurring in skin, breast, thyroid, gastrointestinal tract, endometrium and brain as well as an increased risk of malignant tumours, is associated with an increased breast cancer risk of up to 30 -50% by the age of 70 years.…”

“…In view of the increased cancer risk, intensified screening procedures are indicated. 21,22 Disease-causing 16 Even in families without diffuse gastric cancer in their medical history, CDH1 mutations could be found in women with lobular breast cancer. 24 In view of the increased cancer risk, intensified surveillance programmes are indicated.…”

MLH1 methylation screening is effective in identifying epimutation carriers

“…1,2 It is caused by germline mutations in DNA mismatch repair (MMR) genes. MLH1 or MSH2 are the most commonly mutated MMR genes in LS, whereas mutations in MSH6 or PMS2 are significantly less common.…”

Estimating penetrance from multiple case families with predisposing mutations: extension of the ‘genotype-restricted likelihood’ (GRL) method

“…19,20 In France, 42500 mutations in BRCA1 and BRCA2 were found in index cases and 47000 relatives had genetic testing between 2003 and 2007. For MMR genes, a mutation was found in 41000 index cases and nearly 3000 relatives were tested (http://www.e-cancer.fr/v1/fichiers/public/synthese_ evolution_activite_2003_2007.pdf).…”