Familial Clustering Of Cancer Research Articles

Clinical and molecular characteristics of hereditary non‐polyposis colorectal cancer families in Southeast Asia

Lee S-C, Guo J-Y, Lim R, Soo R, Koay E, Salto-Tellez M, Leong A, Goh B-C. Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Hereditary non-polyposis colorectal cancer (HNPCC), predominantly due to germline MLH1/MSH2 mutations, is the commonest form of hereditary colorectal cancer (CRC), but data in Asians are sparse. We sequenced the MLH1/MSH2 coding and promoter core regions in CRC patients diagnosed below age 40, and/or with multiple primary cancers or familial cancer clustering suggestive of HNPCC, and correlated deleterious mutations with clinical and tumour features. Forty-six Chinese, Malay and Indian kindreds participated. Of the 153 cancers reported in the 46 kindreds, stomach (14%) and urogenital cancers (13%) were the most common extracolonic cancers, whereas endometrial cancer comprised only 7%. Eleven different MLH1 and 12 MSH2 mutations were identified, including nine novel and four recurring mutations in the Chinese. One Indian was a compound heterozygote for an MLH1 and MSH2 mutation. The MLH1/MSH2 mutation data in the Malays and the Indians represents the first in these ethnic groups. Factors strongly associated with deleterious mutations were the Amsterdam criteria, family history of stomach or multiple primary cancers, and MSI-high tumours, whereas family history of endometrial cancer and young cancer age alone correlated poorly. Distinct clinical and molecular characteristics were identified among Asian HNPCC kindreds and may have important clinical implications.

A population-based assessment of the clustering of breast cancer in families eligible for testing of BRCA1 and BRCA2 mutations

BackgroundThe prevalence of families eligible for BRCA1/2 mutation testing in the population burden of breast cancer was analysed and the aggregation of breast cancer in these families was explored. Patients and methodsThe families of the Swedish Family-Cancer Database with at least three generations (N=944723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer for BRCA1/2 mutation testing. We calculated the proportion of women with breast cancer in the classified families and used standardised incidence ratios (SIRs) to estimate the risk of histology specific breast cancers in families with suspected BRCA1/2 mutations. ResultsFamilies with two breast cancers before the age of 50 years included 1.8% of the breast cancer patients; 1% of the women with breast cancer belonged to families with breast and ovarian cancers. The SIR of female breast cancer was lowest in families with male breast cancer and highest in families with two women affected by breast cancer under the age of 50 years. The SIRs of medullary breast cancer agreed with the BRCA1 mutation prevalences detected by the German Consortium for Hereditary Breast and Ovarian Cancer. ConclusionsMost of the breast malignancies in families with male breast cancer are likely to be related to BRCA2 mutations. Non-BRCA1/2 related effects are probably involved in the strong clustering of breast cancer in families with early onset breast and ovarian cancers.

Risk of cancer at sites other than the breast in Swedish families eligible for BRCA1 or BRCA2 mutation testing

Population-based data on the risk of cancer in families eligible for BRCA1/2 mutation testing may help to reach a consensus about the association of BRCA1/2 mutations with cancer at sites other than the breast and may reveal new, non-BRCA1/2 related components of the familial clustering of cancer in those families. The families of the Swedish Family-Cancer Database with at least three generations (n = 944,723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer. The cancer incidences in the classified families were compared with the incidences in the general population. The percentages of individuals with cancer in families eligible for BRCA1/2 mutation testing were compared with data in the literature to estimate the proportion of malignancies related to BRCA1/2 mutations. Families with two breast cancers before the age of 50 years showed increased risk of early onset pancreatic, prostate and ovarian cancers; families with ovarian and breast cancers presented increased incidences for ovarian and ocular cancers; families with two breast cancers, at least one of them under the age of 50 years, showed increased risks of prostate and primary liver cancers. Stomach cancer before age 70 years was twice as frequent in families with breast and ovarian cancers as in the general population. BRCA1/2 mutations probably explain most of the aggregation of ovarian cancer in families with male breast cancer, and in families with at least two breast cancers diagnosed before age 50 years. The association of BRCA1/2 mutations with ovarian, pancreatic, prostate and stomach cancers was confirmed at a population level. However, the clustering of early pancreatic cancer in families with two breast cancers under age 50 years, the aggregation of ovarian cancer in families with breast and ovarian cancers, and the increased incidence of early onset prostate cancer in families with male breast cancer seem to be due to other effects unrelated to BRCA1/2 mutations.

Cancer as a Complex Phenotype: Pattern of Cancer Distribution within and beyond the Nuclear Family

BackgroundThe contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.Methods and FindingsWe have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland.We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.ConclusionWe conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.

Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal inherited cancer syndrome characterized by germline plus somatic mutations of DNA mismatch repair genes and familial clustering of cancers of colorectum and other visceral organs. So far, to our knowledge, there has been no proof of nonepithelial tumors in association with HNPCC. Here we report on a MSH2 frameshift HNPCC family with a carrier found to have multiple primary tumors, including endometrial hyperplasia, ovarian adenocarcinoma, skin cavernous hemangioma, and skin dermatofibrosarcoma protuberans (DFSP). We studied the replication error (RER) phenotype in noncoding (Bat-26, Bat-25, D2S123, D5S346, and D17S250) and coding ( MSH3, MSH6, BAX, and TGFBR2 genes) DNA sequences, and characterized the germline and somatic mutations of the MSH2 gene in the tumors described above and in endometrial carcinomas from two of her affected siblings. RER was observed in an order of hyperplasic endometrium (6/10 markers), ovarian carcinoma (5/10 markers), endometrial carcinomas (4/9 and 3/10), DFSP (2/9 markers), and cavernous hemangioma (2/10 markers). All the tumors showed the same germline mutation of G5→G6 frameshift at 183–187 and polymorphism of C1168T in a heterozygous pattern. In an endometrial carcinoma, deletion of the second allele of MSH2 was evident. Heterogeneous RER patterns were noted in multiple primary tumors of the same individual and in premalignant and malignant endometrial tumors from different individuals. The study demonstrated the two hits of the hMSH 2 gene as well as intra- and interindividual variations of RER phenotypes in HNPCC. The first characterized nonepithelial tumors in HNPCC seem to carry a limited panel of RER, including a framesift at the (A) 10 tract of TGFBR2.

Genetic epidemiology of cancer: from families to heritable genes.

A reliable determination of familial risks for cancer is important for clinical counseling, prevention and understanding cancer etiology. Family-based gene identification efforts may be targeted if the risks are well characterized and the mode of inheritance is identified. Medically verified data on familial risks have not been available for all types of cancer but they have become available through the use of the nationwide Swedish Family-Cancer Database, which includes all Swedes born in 1932 and later with their parents, totaling over 10 million individuals. Over 150 publications have emanated from this source. The familial risks of cancer have been characterized for all main cancers and the contribution of environmental and heritable effects to the familial aggregation has been assessed. Furthermore, the mode of inheritance has been deduced by comparing risks from parental and sibling probands. Examples are shown on familial clustering of cancers, for which heritable susceptibility genes are yet unknown, such as squamous cell carcinoma of the skin, intestinal carcinoids, thyroid papillary tumors, brain astrocytomas and pituitary adenomas. Some common cancers, such as lung and kidney cancers, appear to show an early-onset recessive component because familial risks among siblings are much higher than those in families where parents are probands. Many of the cancer sites showing high familial risks lack guidelines for clinical counseling or action level. In conclusion, we recommend that any future gene identification efforts, either using linkage or association designs, devise their strategies based on data from family studies. Clinical genetic counseling would benefit from reviewing established familial risks on all main types of cancer.

The epidemiology of laryngeal cancer in Brazil

The city of São Paulo exhibits one of the highest incidences of laryngeal cancer in world and Brazil presents remarkable occurrence, compared with other Latin American countries. Around 8,000 new cases and 3,000 deaths by laryngeal cancer occur annually in the Brazilian population. In the city of São Paulo, incidence rates for laryngeal cancer among males have been decreasing since the late 1980s while, among females, the rates have shown a stable trend. This phenomenon is probably the expression of changes in gender behavior related to tobacco smoking. Several risk factors are involved in the genesis of laryngeal cancer. The most important are tobacco smoking and alcohol intake, but occupational hazards have also been associated with the disease, such as asbestos, strong inorganic acids, cement dust and free crystalline silica. Additionally, salted meat and total fat intake have been linked to elevated risk of laryngeal cancer. Conversely, several studies have confirmed that fruits, raw leaf vegetables and legumes protect against this cancer. Some researchers have postulated a possible association between laryngeal squamous cell carcinoma and human papilloma virus (HPV), but this is not universally accepted. Gastroesophageal reflux disease is weakly, but consistently correlated with laryngeal cancer. Familial cancer clusters, particularly of head and neck tumors, seem to increase the risk of laryngeal cancer. Some genetic polymorphisms, such as of genes that code for xenobiotic-metabolizing enzymes, have shown elevated risk for laryngeal cancer according to recent studies. Public health policies regarding the control of tobacco smoking and alcohol consumption, and also surveillance of carcinogen exposure in occupational settings, could have an impact on laryngeal cancer. No proposals for screening have been recommended for laryngeal cancer, but one diagnostic goal should be to avoid treatment delay when suspected symptoms have been observed.

MSI in endometrial carcinoma: Absence of MLH1 promoter methylation is associated with increased familial risk for cancers

Loss of DNA mismatch repair occurs in a variety of malignancies and is associated with genome-wide instability of microsatellite repeats, a molecular phenotype referred to as microsatellite instability (MSI). MSI is a consistent feature of colorectal and endometrial tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC). Sporadic colorectal and endometrial cancers that exhibit MSI frequently have methylation of the MLH1 promoter. We undertook a detailed family and medical history study to compare family cancer risk for women with MSI-positive and -negative endometrial cancers. The MLH1 promoter methylation status was determined for all cancers. Family histories were developed for 80 probands (40 with MSI-positive and 40 with MSI-negative tumors). The numbers of reported cancers in first- and second-degree relatives of the 2 groups were similar. There was a modest increase in familial cancer clustering for MSI-positive probands. When MSI-positive tumors were subclassified according to MLH1 promoter methylation, a clear association between methylation status and familial cancer risk was evident. Women with MSI-positive endometrial cancers in which the MLH1 promoter was unmethylated had a 7-fold relative risk (RR) of demonstrating familial clustering of cancers [RR 7.07 (95% confidence interval 2.29-21.81)]. The women with MSI-positive, MLH1-unmethylated tumors were significantly younger than the rest of the study population (56.1 years vs. 65.4, p < or = 0.01). Age of onset and tumor MSI not associated with MLH1 promoter methylation may point to women with a genetic susceptibility to malignancies.

Segregation analysis of cancer in families of glioma patients.

A small proportion of brain tumors are attributed to a genetic predisposition; however, the hereditary proportion is undetermined. This study evaluates the degree of familial aggregation of cancer in a large series of brain tumor patients. Our study included 5,088 relatives of 639 probands (3,810 first- and 1,278 second-degree), diagnosed with a glioma between June 1992 and June 1995 at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, with diagnosis under age 65 years, and residents of the United States or Canada. We conducted an in-person or telephone interview with patients and/or their next-of-kin, and obtained family histories for the probands' first-degree (parents, siblings, offspring) and selected second-degree relatives (aunts, uncles, grandparents) using a sequential sampling strategy. Reported cancers were documented by medical records and/or death certificates (if the relative was deceased and medical records were unavailable). We conducted segregation analysis using the Pedigree Analysis Program (PAP). The analyses were divided into two categories: (1) all 639 families, and (2) a subset of families whose gliomas stained positive on p53 immunohistochemistry analysis. We demonstrated that a multifactorial Mendelian model was favored, while a model postulating a purely environmental cause of brain cancer was rejected. This study indicates that familial cancer in relatives of glioma patients are probably a result of multigenic action, and familial clustering of cancer among relatives of glioma patients may involve unknown environmental exposures.

Microsatellite instability—a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer

BACKGROUNDClinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the...

Microsatellite instability in female non-small-cell lung cancer patients with familial clustering of malignancy.

There is accumulating evidence of an increased risk of familial clustering of cancer in the first-degree relatives of lung cancer probands. However, no explanation has been proposed for these epidemiological data. We reviewed 379 female non-small-cell lung cancer (NSCLC) patients to obtain their family histories of malignancy. Among them, nine female NSCLC patients with three or more relatives diagnosed with malignancy and 28 control patients without a family history of malignancy were selected to be analysed for instability at six different microsatellite loci. We observed microsatellite instability (MSI) more frequently in the patients with three or more family histories of malignancy (six out of nine, 67%) than the control patients (5 out of 28, 18%). The incidence of MSI in the former was significantly higher than that in the control (P=0.011: Fisher's exact test). We detected no significant difference in clinicopathological characteristics between the cases with MSI and those without MSI, except for their family histories of cancer. Our results show that a significantly higher rate of MSI is associated with familial clustering of malignancy. MSI could be one of the underlying mechanisms for familial clustering of malignancy in female NSCLC patients.

Familial cancer in Sweden

Studies on familial clustering of cancer have usually followed transmission of a trait or mutant gene from one parental line. However, an access to families with two affected parents may additionally contribute to the models of carcinogenesis. The combined effect of parental cancer on the cancer risk of the offspring was tested in a large population-based data set. A family-cancer data base was constructed from the nationwide Swedish registries to include over 21,000 cancers in offspring diagnosed at ages 15-51 and their parents. Cancer risk in the offspring was assessed when the parents had different combinations of site-specific cancers. The risk in the offspring was increased only moderately, at most 1.1 times when the father or the mother had cancer. If both parents had cancer the risks were higher and reached statistical significance for the following paternal/maternal site-specific combinations: colorectum/colorectum, prostate/colorectum, colorectum/breast, prostate/breast, melanoma/breast and skin (squamous cell carcinoma)/breast. These results on young and middle-aged adults indicate that cancer in both parents increase cancer risk in the offspring at many sites. A likely molecular explanation is that both parents contribute with different mutant genes to the set of genes constituting the multistage pathway to carcinogenesis.

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.

Detection of microsatellite instability in human colorectal carcinomas using a non-radioactive PCR-based screening technique.

The aim of the present study was to establish a rapid, non-radioactive screening method for the detection of microsatellite instability (MIN). MIN is the primary characteristic of the mutator phenotype in tumours constituting hereditary non-polyposis colon cancers (HNPCC). We investigated 30 patients suffering from colorectal cancer using a non-radioactive PCR-based technique. MIN was present in 7 of 30 (23%) of the cases. There was a statistically significant correlation between MIN and localization of the tumour. Five of 7 (72%) tumours with MIN but only 4 of 23 (17%) tumours without MIN were localized in the proximal colon (P < 0.01). There was a tendency to higher MIN frequency in tumours of patients with familial clustering of cancers. However, this was statistically not significant (P > 0.05). In addition, no correlation between MIN and tumour grade and stage was found. For the investigations in the present study we used a non-radioactive PCR-based method followed by denaturating polyacrylamide gel electrophoresis and silver staining. This method is highly sensitive and reproducible. Thus, PCR-based analysis using a non-radioactive staining technique represents a comprehensive tool for MIN screening in diagnostic pathology.

Genes and family environment in familial clustering of cancer

Familial clustering of a disease is defined as the occurrence of the disease within some families in excess of what would be expected from the occurrence in the population. It has been demonstrated for several cancer types, ranging from rare cancers as the adenomatosis-coli-associated colon cancer or the Li-Fraumeni syndrome to more common cancers as breast cancer and colon cancer. Familial clustering, however, is merely an epidemiological pattern, and it does not tell whether genetic or environmental causes or both in combination are responsible for the familial clustering. Familial clustering may be due to genetic predisposition to the disease, but exposure to environmental factors--shared by members of some families, but not by members of other families--may also cause familial clustering and hence mimic genetic inheritance in the study of nuclear families. Based on assumptions regarding the individual steps in the biological process starting with exposure to carcinogens and ending with death from disseminated cancer we suggest that genetic and environmental factors may both be involved in most of these steps. The present paper focuses on research methodologies necessary to discriminate between the effect of genes and family environment in the development of cancer.

Familial cancer syndromes and clusters.

The study of rare families in which a variety of cancers occur, usually at an early age and with patterns consistent with a common hereditary mechanism, has contributed much to our understanding of the process of carcinogenesis. So far, genes identified as having a role in cancer predisposition in these families have also been important in the histogenesis of sporadic cancers. In the two most clearly defined cancer family syndromes, the Li-Fraumeni syndrome and Lynch syndrome II, the genes involved predispose to diverse but specific constellations of cancers. Genes associated with site-specific familial cancer clusters may also give rise to increased susceptibility to other cancers, and site-specific clusters may represent one end of a spectrum. A consistent feature of familial cancer syndromes is the variable expression within and between families. A challenge for the future will be to determine other factors which may interact with the principal genes involved, giving rise to this variability.

Familial Ovarian Cancer

Familial cancer clusters provide a unique opportunity to elucidate the molecular mechanisms central to the development of malignancy. We have identified four families in which 11 members developed epithelial ovarian cancer. The clinical course of disease in these individuals with familial ovarian cancer appears to be very different from that of patients with nonfamilial ovarian cancer. In order to compare these disease states, 34 cases matched for age at diagnosis (57 years), tumor histology (all adenocarcinomas), and a preponderance of advanced grade and FIGO stage of disease were selected. Patients with familial ovarian cancer exhibited a 67% 5-year survival in comparison with a 17% 5-year survival in the nonfamilial ovarian cancer cases. Preliminary studies indicate a lack of overexpression of the HER-2/neu oncogene in the familial cancer members' tumors. This may correlate with the indolent character of their disease. Abnormal p53 tumor suppressor gene expression was noted in four of six cancers tested. We also found germ line p53 mutations in three of the four families, but neither the germ line or tumor p53 prevalence was 100%. This is the first report of germ line p53 mutations associated with familial ovarian cancer and indicates that this gene may play a role in the development of some familial ovarian cancers.

Lung cancer histologic types and family history of cancer. Analysis of histologic subtypes of 872 patients with primary lung cancer

Previous research has demonstrated that there is clustering of cancer among relatives of patients with lung cancer and that women may be at a greater risk than men, regardless of their smoking histories. The authors conducted a study to test the hypotheses that this predisposition varies by the histologic type of tumor and that women with particular histologic types will report more first-degree relatives with cancer than will men with the same cell type. The analyses were based on 872 patients with histologically confirmed lung cancer who had been admitted to Roswell Park Cancer Institute, Buffalo, New York, between 1982 and 1987. More patients with squamous and large cell carcinomas reported two or more relatives with cancer, and overall, women reported more family history of cancer. Among patients with squamous cell carcinoma, this difference between men and women was significant (P < 0.05). Among patients younger than 57 years, those with squamous cell were the most likely to report a family history of cancer (P < 0.01). A similar trend was observed for smoking. Persons with small cell and squamous cell carcinomas who were nonsmokers or had smoked 1-20 years had three times the risk of a family history of cancer than did those with large cell and adenocarcinomas (odds ratio [OR] = 3.01; confidence interval [ci] = 1.38-6.63), in contrast to those who had smoked more than 20 years (OR = 0.85; ci = 0.62-1.62). Squamous cell carcinoma is most associated with familial clustering of cancer, particularly among women, persons younger than 57 years, and individuals who smoked for fewer than 20 years.

Clustering of cancer in families of patients with primary lung cancer

We have previously shown that patients with a positive family history of lung cancer did not exhibit characteristics expected if the familial association was a surrogate for a genetic mechanism which was absent in those without such a history. In this study, we examine the incidence of cancer (all sites) in two groups of families: (a) those ascertained through a patient with primary lung cancer ( n = 359 families) and (b) through a community control subject ( n= 234). The index subjects were excluded from all incidence data analyses. Most families (62 vs 57%) reported at least one member with a history of neoplastic disease. Patients' families were more likely to have 2 or more affected members ( p < 0.05), to exhibit a multigenerational pattern (33 vs 24%) and to have a higher risk of multiple tumours (OR = 1.5) in the same individual. However, most of the sites with the highest odds ratios (males, vocal cord/esophagus 8.3; colon/rectum 2.3; lung 1.96; females, pancreas 4.8; vocal/cord esophagus 4.1; lung 1.8) are smoking associated although these were not necessarily the most frequently affected sites. In conclusion, these data support an ecogenetic etiology of cancer within families.

BREAST-CANCER-PRONE FAMILIES

Three breast-cancer-prone families are reported. It is strongly suggested that familial clustering of breast cancer is related to genetic factors. In family S, five family members of two generations were diagnosed as having breast cancer, and one had thyroid cancer metachronously. In family K, four family members of two generations were diagnosed as having breast cancer, and moreover, gastric cancer, colon cancer, uterine cancer and ovarian cancer were seen in family members. In family A with a breast cancer patient as the proband, gastric cancer, colon cancer, uterine cancer and ovarian cancer were seen in six members of two generations. According to an analysis of the organs from which cancer originated in these three cancer-prone families, it was suggested that there was only chronological difference between breast-cancer-prone families with organ specificity and other cancer-prone families. The clinical significance noting familial clustering of cancer is to detect high-risk groups for cancer. Screening and follow-up of the members of cancer-prone families may help to detect early cancerous lesions and to make early therapeutic decisions.