Hereditary breast cancer: part I. Diagnosing hereditary breast cancer syndromes

Abstract:  Hereditary breast cancer (HBC) accounts for as much as 10% of the total BC burden. Most of these cases will be found to be due to a BRCA germline mutation. An estimated additional 15–20% of those affected with BC will have one or more first- and/or second-degree relatives with BC. Therefore, when these numbers are combined, familial BC risk accounts for approximately 20–25% of the total BC burden. However, because of the often limited information on family history in the etiologic assessment of BC, this may be an underestimate. Confounding factors include its phenotypic and genotypic heterogeneity, given the association of HBC with a plethora of differing cancer syndromes. Its most common occurrence is its association with ovarian cancer in the so-called hereditary breast-ovarian cancer syndrome due to BRCA1 and BRCA2 mutations. More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma. Importantly, the age-adjusted incidence of BC in women in the United States fell sharply, by 6.7%, in 2003, when compared with the rate identified in 2002. We postulate that increasing knowledge about the genetics of BC may have partially contributed to the identification of high-risk patients who thereby may have benefited significantly from early diagnosis.     

Hereditary urological cancer syndromes

Hereditary urological cancer syndromes are rare, but it is important that they are recognized because they have important prognostic implications; prompt diagnosis can dramatically improve patient outcomes. The urologist or urological oncologist should, therefore, ascertain which tumors of the many seen in clinical practice warrant referral for the opinion of a clinical geneticist. Despite the aggressive natural history of most inherited urological cancer syndromes, organ-preserving treatments are desirable because these syndromes predispose affected patients to the formation of multifocal and metachronous tumors. Identification of the molecular mechanisms that underlie carcinogenesis in both familial and sporadic urological cancers has, in some cases, resulted in novel and specifically targeted approaches to therapy. Patients who present with early-onset or multiple tumors should be carefully investigated for the presence of a hereditary cancer syndrome, and once a diagnosis is made, appropriate screening should be instigated for family members to enable early detection of tumors both within and outside the urogenital tract.     

Hereditary colorectal cancer associated with polyposis syndromes

This study reviews different aspects of hereditary colorectal cancer associated with three polyposis syndromes: familial adenomatous polyposis, juvenile polyposis coli and Peutz-Jeghers syndrome. All these syndromes share some similarities: low incidence, autosomal dominant inheritance, genetic predisposition to colorectal cancer and/or other extracolonic cancers. Classical familial adenomatous polyposis is clinically defined by the presence of hundreds of adenomatous polyps in the colon and rectum, whereas less than 100 polyps are found in attenuated familial adenomatous polyposis. Without prophylactic colectomy, colorectal cancer develops inevitably by the age of 40. Restorative proctocolectomy with ileal anal-pouch anastomosis is the operation of choice in familial adenomatous polyposis. In juvenile polyposis coli, 50-200 hamartomatous polyps are found in the colon, rectum, stomach and small bowel. Life-time cumulative risk for colorectal cancer is estimated to be 50%. Prophylactic colectomy is required only in cases in which endoscopic surveillance is not able to control polyp development. Hereditary mixed polyposis syndrome is a variant form of juvenile polyposis coli, consisting of multiple mixed adenomatous, hyperplastic and hamartomatous polyps. Peutz-Jeghers syndrome is characterized by multiple hamartomatous polyps located in the small bowel, colon and stomach. Small bowel follow through and colonoscopy is advised for surveillance. Surgery is warranted only in cases of polyps larger than 1 cm. The causative genes of these syndromes have been cloned. Molecular genetic testing of affected and at-risk individuals is proposed in order to advise surveillance and management.     

Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome

Familial colorectal cancer (CRC) accounts for 10% to 20% of all cases of CRC. Two major autosomal dominant forms of heritable CRC are familial adenomatous polyposis (FAP) and Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). Along with the risk for CRC, both syndromes are associated with elevated risk for other tumors. Improved understanding of the genetic basis of these diseases has not only facilitated the identification and screening of at-risk individuals and the development of prophylactic or early-stage intervention strategies but also provided better insight into sporadic CRC. This article reviews the clinical and genetic characteristics of FAP and Lynch syndrome, recommended screening and surveillance practices, and appropriate surgical and nonsurgical interventions.     

Hereditary gastrointestinal polyposis syndromes

Hereditary gastrointestinal polyposis syndromes can be divided into adenomatous and hamartomatous types. Familial adenomatous polyposis coli (FAPC) is the prototype adenomatous polyposis syndrome and is defined by the autosomal dominant transmission of multiple (more than 100) colorectal adenomas. Virtually all affected patients develop colorectal carcinoma if untreated. Adenomas may develop also in the stomach and small bowel in FAPC patients, but the incidence of carcinoma in these sites is low. A variety of extracolonic manifestations has been reported in FAPC, with the name Gardner's syndrome applied to kindreds with osteomas of the skull and mandible, multiple epidermal cysts, and other skin and soft-tissue lesions. In Turcot's syndrome, brain tumors are present. The distinction between Gardner's and Turcot's syndromes and classical FAPC has become blurred because of marked overlap between them; some authorities consider them to be varying manifestations of a single genetic defect. The hamartomatous polyposes include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, intestinal ganglioneuromatosis, and the Ruvalcaba-Myrhe-Smith syndrome. The incidence of gastrointestinal cancer in patients with Peutz-Jeghers syndrome and familial juvenile polyposis exceeds that in the normal population, but is relatively low. In Cowden's disease, the gastrointestinal tract may be the site of multiple hamartomas, but there is no associated increase in the incidence of gastrointestinal cancers; instead, there is an increased incidence of carcinoma of the breast and thyroid. Intestinal ganglioneuromatosis occurs in von Recklinghausen's disease, in association with multiple endocrine neoplasia, type 2b, or as an isolated abnormality. Patients with ganglioneuromatosis do not appear to have an increased risk of developing gastrointestinal cancer. Ruvalcaba-Myrhe-Smith syndrome comprises macrocephaly, mental deficiency, an unusual craniofacial appearance, hamartomatous intestinal polyposis, and pigmented macules on the penis. No increased risk of developing cancer has been identified in the few reported cases.     

Hereditary colorectal cancer: observations of a family study]

Described in Switzerland in the early '60, the major features of hereditary non-polyposis colon cancer syndrome (HNPCCS) were established 20 years ago by H. T. Lynch. HNPCCS accounts for at least 60% of the colon cancer etiology. Cancer family syndrome is defined by the presence of extracolonic primary tumors in addition to colon cancer. Both syndromes are transmitted by an autosomic dominant pattern. None of the known biomarkers are specific and/or sensitive enough to rely on their predictive values of patient's risks. A typical Swiss family was investigated on the basis of the cancer-prone family history. 21% of the family members observed over 5 generations presented one or more (30% of the cases) colo-rectal neoplasms at the age of 50. 55% of the tumors were right sided. Histologically, half of the tumors were mucinous. 30% of metachronous cancer appeared within 10 years. Polyps (1-3) and flat adenomas were associated to the lesion in 57%. Extra-colonic tumors appeared in 18% of family members and in half of the colon cancer patients. The sites of these tumors were the urinary tract, ovary, small bowel, breast and stomach. Two fibroblast strains of affected individuals were established. No increased tetraploidy was noted. Preliminary results suggest that this two strains are rather sensitive to ionising radiation. Often neglected, family history of colon cancer remains the major diagnostic and decision-making tool of a such syndrome. It will necessitate special treatment of affected subjects and early screening of the relatives.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hereditary hemolytic uremic syndromes and thrombotic thrombocytopenic purpura

During the last decade, major progresses have been performed in the understanding and classification of hereditary haemolytic uremic syndromes and thrombotic thrombocytopenic purpura. The identification of patients with congenital thrombotic thrombocytopenic purpura due to hereditary deficiency of von Willebrand factor protease (Adamts 13) is of primordial importance, as fresh frozen plasma infusions prevent relapses and the risk of visceral (mainly cerebral and renal) involvement. The identification of patients with haemolytic uremic syndromes due to mutations in the genes that encode complement alternative pathway regulatory proteins (factor H, factor I, MCP) opens the way to new physiopathologic and therapeutic advances.     

Hereditary breast cancer: part II. Management of hereditary breast cancer: implications of molecular genetics and pathology

Abstract:  Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation-positive breast cancers wherein those with BRCA1 mutations are frequently estrogen receptor (ER)-negative in contrast to BRCA2 mutations which are more frequently ER-positive; therein, significant differences exist with respect to anti-estrogen therapy which will be more amenable to BRCA2 versus BRCA1 mutation carriers manifesting breast cancer. In turn, tumors that are negative for ER, PR, and Her2-neu, often referred to as "triple negative" tumors, may also harbor a unique basal-like gene expression profile and are characterized by poor prognosis wherein endocrine and/or Her2-neu-targeted therapies are not effective treatment options. A further confounder pertains to the lifetime risk for ovarian cancer, which differs strikingly between BRCA1 mutation carriers, who show a 40–60% lifetime risk, and their BRCA2 counterparts, who carry a lifetime risk of approximately 12–15% for ovarian cancer. It is clear that as we learn more about the biology and the molecular aspects of hereditary forms of breast cancer, it will be compelling for the clinician to integrate this knowledge with pharmacologic, radiologic, and surgical treatment options for these high-risk patients.     

Hereditary and familial cancer

Advances in both access to and the technology underpinning next-generation sequencing have provided a formidable basis for the evaluation of individuals and families recognized as having a potential hereditary cancer. This article focuses on the most clinically relevant hereditary cancer predisposition syndromes such as hereditary breast and ovarian cancer syndromes and hereditary colorectal cancer. It also reviews current best practice in both surveillance for affected individuals as well as an providing an overview of the available risk-reduction strategies for affected individuals.     

Hereditary and familial cancer

Advances in both access to and the technology underpinning next-generation sequencing have provided a formidable basis for the evaluation of individuals and families recognized as having a potential hereditary cancer. This article focuses on the most clinically relevant hereditary cancer predisposition syndromes such as hereditary breast and ovarian cancer syndromes and hereditary colorectal cancer. It also reviews current best practice in both surveillance for affected individuals as well as an providing an overview of the available risk-reduction strategies for affected individuals.     

Hereditary carcinoma syndromes associated with benign head and neck tumors

Hereditary forms of carcinoma may be associated with benign head and neck tumors. Many of these hereditary carcinoma syndromes present first to the otolaryngologist. Two unusual cases of Gardner's and Muir--Torre's syndromes illustrate the hereditary carcinoma syndromes associated with head and neck lesions. We describe the use of new genetic markers and propose a diagnostic algorithm.     

Lumpectomy and breast radiotherapy in breast cancer patients with a family history of breast cancer,ovarian cancer,or both

This article presents an outcomes review of breast cancer patients identified from the cancer registries of four area hospitals. These patients had family histories of breast cancer, ovarian carcinoma, or both and were treated with conservative surgery and radiation to the involved breast. Patients were as follows: group 1, one first-degree relative ( n = 165, one synchronous bilateral breast cancer); group 2, ≥2 first-degree relatives ( n = 21); group 3, one second-degree relative ( n = 20); and group 4, ≥2 second-degree relatives ( n = 18). The total of patients and breast cancer events was 224 and 225, respectively. Group 5 was a subgroup of 53 patients with a substantial risk (>10%) of a BRCA1 or BRCA2 mutation. After a median follow-up of 3.9 years, 5 patients had local failure (2%), and 5 developed a contralateral breast cancer (2%). There were no significant differences in local failure rates between groups (p = 1.0): group 1, 5 of 166 (3%); group 2, 0 of 21 (0%); group 3, 0 of 20 (0%); and group 4, 0 of 18 (0%). Local failure for group 5 was 2% (1 of 53). Four of 143 patients (3%) with a minimum 3 years of follow-up (median, 5.6 years) had local failure, and 5 (4%) developed a contralateral breast cancer. A univariate analysis was statistically significant for differentiation only (well, 0 of 67; moderately, 1 of 57 [1.8%]; poor, 3 of 26 [11.5%], p = 0.008). Overall survival for groups 1–4 did not differ significantly. Although follow-up has been relatively short, we have not found that breast cancer patients with various degrees of family histories of breast/ovarian carcinoma have had a detrimental outcome when treated with conservative therapy.     

Hereditary kidney cancer

Significant advances have been made in the understanding of the genetic basis of familial renal neoplasia. Identification of key genes in the pathogenesis of various hereditary renal cancer syndromes has provided opportunities to screen family members at risk and to explore the significance of these genetic abnormalities in the development and genesis of much more common sporadic counterparts. As researchers continue to delineate critical carcinogenic pathways and accumulate expansive knowledge on oncogenic mechanisms driving cancer initiation and progression at the cellular and molecular levels, this information will be integrated and translated into effective diagnostic and therapeutic strategies that will dictate clinical management of all renal cancers.