Li–Fraumeni syndrome (LFS) is relatively rare; as of 2011, cases had been reported in more than 500 families. The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome. Identification of TP53 as the gene affected by mutation was suggested by the same approach. Over half of the cancers in Li-Fraumeni families had been previously associated with inactivating mutations of the p53 gene and in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated TP53 gene.

A 2009 revision of the traditional Chompret criteria for screening has been proposed:

A proband who has:

- tumor belonging to the LFS tumor spectrum - soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia or lung bronchoalveolar cancer - before age 46 years;

and at least one of the following:

- at least one first or second degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumours

- a proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before age 46 years

- a proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history

Muir–Torre was observed to occur in 14 of 50 families (28%) and in 14 of 152 individuals (9.2%) with Lynch syndrome, also known as HNPCC.

The 2 major MMR proteins involved are hMLH1 and hMSH2. Approximately 70% of tumors associated with the MTS have microsatellite instability. While germline disruption of hMLH1 and hMSH2 is evenly distributed in HNPCC, disruption of hMSH2 is seen in greater than 90% of MTS patients.

Gastrointestinal and genitourinary cancers are the most common internal malignancies. Colorectal cancer is the most common visceral neoplasm in Muir–Torre syndrome patients.

Birt-Hogg-Dubé Syndrome patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

In the United States, the annual incidence of chordoma is approximately 1 in one million (300 new patients each year).

There are currently no known environmental risk factors for chordoma. As noted above germline duplication of brachyury has been identified as a major susceptibility mechanism in several chordoma families.

While most people with chordoma have no other family members with the disease, rare occurrences of multiple cases within families have been documented. This suggests that some people may be genetically predisposed to develop chordoma. Because genetic or hereditary risk factors for chordoma may exist, scientists at the National Cancer Institute are conducting a Familial Chordoma Study to search for genes involved in the development of this tumor.

A 2006 review stated that RS often leads renal cancer between ages 30-50. Renal cancer kills about 1 in 3 people, but 5-year survival rates improved between 1974-1976 and 1995-2000, from 52% to 64%.

Hereditary cancer syndromes underlie 5 to 10% of all cancers. Scientific understanding of cancer susceptibility syndromes is actively expanding: additional syndromes are being found, the underlying biology is becoming clearer, and commercialization of diagnostic genetics methodology is improving clinical access. Given the prevalence of breast and colon cancer, the most widely recognized syndromes include hereditary breast-ovarian cancer syndrome (HBOC) and hereditary non-polyposis colon cancer (HNPCC, Lynch syndrome).

Some rare cancers are strongly associated with hereditary cancer predisposition syndromes. Genetic testing should be considered with adrenocortical carcinoma; carcinoid tumors; diffuse gastric cancer; fallopian tube/primary peritoneal cancer; leiomyosarcoma; medullary thyroid cancer; paraganglioma/pheochromocytoma; renal cell carcinoma of chromophobe, hybrid oncocytic, or oncocytoma histology; sebaceous carcinoma; and sex cord tumors with annular tubules. Primary care physicians can identify people who are at risk of heridatary cancer syndrome.

The disorder has been reported in more than 100 families worldwide, though some sources cite up to 400 families, and it is inherited in an autosomal dominant pattern. It is considered to be under-diagnosed because of the variability in its expression. The pattern of mutations and spectrum of symptoms are heterogeneous between individuals. Less severe skin phenotypes are seen in women and people of both sexes who have a late onset of skin symptoms.

A cancer syndrome or family cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancers and may also cause the early onset of these cancers. Cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors. Many of these syndromes are caused by mutations in tumor suppressor genes, genes that are involved in protecting the cell from turning cancerous. Other genes that may be affected are DNA repair genes, oncogenes and genes involved in the production of blood vessels (angiogenesis). Common examples of inherited cancer syndromes are hereditary breast-ovarian cancer syndrome and hereditary non-polyposis colon cancer (Lynch syndrome).

Screening for melanoma in FAMMM kindreds should begin at age 10 with a baseline total body skin examination including scalp, eyes, oral mucosa, genital area, and nail, as family members may develop melanoma in their early teens.

At Mayo Clinic, FAMMM patients with a confirmed mutation and family history of pancreatic cancer are offered screening with either high-resolution pancreatic protocol CT, MRI, or endoscopic ultrasound starting at age 50 or 10 years younger than the earliest family member with pancreas cancer. They are counseled on the lack of evidence-based data to support screening, and on the limitations of our current technology to detect a lesion at a stage amenable to therapy.

Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome (after Jacques Turcot, who described the condition in 1959) and by several other names.

In MMRCS, neoplasia typically occurs in both the gut and the central nervous system (CNS). In the large intestine, familial adenomatous polyposis occurs; in the CNS, brain tumors.

A number of genes are associated with HBOC. The most common of the known causes of HBOC are:

- BRCA mutations: Harmful mutations in the "BRCA1" and "BRCA2" genes can produce very high rates of breast and ovarian cancer, as well as increased rates of other cancers.

Other identified genes include:

- "TP53": Mutations cause Li-Fraumeni syndrome. It produces particularly high rates of breast cancer among younger women with mutated genes, and despite being rare, 4% of women with breast cancer under age 30 have a mutation in this gene.

- "PTEN": Mutations cause Cowden syndrome, which produces hamartomas (benign polyps) in the colon, skin growths, and other clinical signs, as well as an increased risk for many cancers.

- "CDH1": Mutations are associated with lobular breast cancer and gastric cancer.

- "STK11": Mutations produce Peutz–Jeghers syndrome. It is extremely rare, and creates a predisposition to breast cancer, intestinal cancer, and pancreatic cancer.

- "CHEK2": Approximately one out of 40 northern Europeans have a mutation in this gene, making it a common mutation. Considered a moderate-risk mutation, it may double or triple the carrier's lifetime risk of breast cancer, and also increase the risk of colon cancer and prostate cancer.

- "ATM": Mutations cause ataxia telangectasia; female carriers have approximately double the normal risk of developing breast cancer.

- "PALB2": Studies vary in their estimate of the risk from mutations in this gene. It may be moderate risk, or as high as "BRCA2".

Approximately 45% of HBOC cases involve unidentified genes, or multiple genes.

Under the name constitutional mismatch repair-deficiency, (CMMR-D), it has been mapped to MLH1, MSH2, MSH6 or PMS2. Although these are the same genes mutated in the condition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer, the mutations are biallelic in CMMR-D.

The term "childhood cancer syndrome" has also been proposed.Café-au-lait macules have been observed.

In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.

Dysplastic nevus syndrome (also known as "atypical mole syndrome (AMS)", "familial atypical multiple mole–melanoma (FAMMM) syndrome", "familial melanoma syndrome", and "B-K mole syndrome") is a cutaneous condition described in certain families, and characterized by unusual nevi and multiple inherited melanomas.

Other relatively rare conditions have been reported in association with this disease. It is not yet known if these associations are fortuitous or manifestations of the condition itself.

Cerebral cavernomas and massive, macronodular adrenocortical disease have also been reported in association with this syndrome. A case of cutis verticis gyrata, disseminated collagenoma and Charcot-Marie-Tooth disease in association with a mutation in the fumarate hydratase gene has also been reported. Two cases of ovarian mucinous cystadenoma have also been reported with this mutation.

A couple studies have been conducted on patients with both Muir–Torre syndrome and Turcot syndrome. It is thought that the two may have some genetic overlap. Both have been associated defects in MLH1 and MSH2 genes.

In one study, a patient with defective MSH2 and MSH6 mismatch repair genes exhibited both syndromes. This is the first case where a patient with genotypic changes consistent with HNPCC has been properly diagnosed with an overlap of both syndromes. Along with neoplasms of the sebaceous gland, this patient developed cerebral neoplasms, characteristic of Turcot syndrome.

Most juvenile polyps are benign, however, malignancy can occur. The cumulative lifetime risk of colorectal cancer is 39% in patients with juvenile polyposis syndrome.

Gardner syndrome is inherited in an autosomal dominant manner. Typically, one parent has Gardner syndrome. Each of their children, male and female alike, are at 50% risk of inheriting the gene for Gardner syndrome.

Hereditary breast–ovarian cancer syndromes (HBOC) are cancer syndromes that produce higher than normal levels of breast cancer and ovarian cancer in genetically related families (either one individual had both, or several individuals in the pedigree had one or the other disease). The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family.

Childhood rhabdomyosarcoma has been fatal. Recovery rates have increased by 50 percent since 1975. In children five years of age or younger survival rates are up to 65 percent. In adolescents younger than 15 years old, the survival rate has increased up to 30 percent.

The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births.

By age 35 years, 95% of individuals with FAP (>100 adenomas) have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34–43 years).

Attentuated FAP arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated FAP manifests as colorectal cancer unusually late (age 40–70, average=55), and typically with few, or at least far fewer polyps (typically 30), than the more usual version of FAP, at an age when FAP is no longer considered much of a likelihood or risk according to usual FAP epidemiology.

Gardner syndrome is caused by mutation in the adenomatous polyposis coli (APC gene), located in chromosome 5q21 (band q21 on chromosome 5). This gene is also mutant in familial adenomatous polyposis (FAP), a more common disease that also predisposes to colon cancer. Nuances in the understanding of genetics have caused some disorders to be split into multiple entities, while others merged into one genetic condition. After most of the second half of the 20th century, Gardner syndrome has been merged into FAP and is now considered simply a phenotypic subtype of FAP.

DNA damage is considered to be the primary cause of cancer. More than 60,000 new naturally occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes (see article DNA damage (naturally occurring)).

Additional DNA damages can arise from exposure to exogenous agents. As one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, and these DNA damages likely cause the increase of lung cancer due to smoking. In other examples, UV light from solar radiation causes DNA damage that is important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, and the Aspergillus metabolite, aflatoxin, is a DNA damaging agent that is causative in liver cancer.

DNA damages can also be caused by endogenous (naturally occurring) agents. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis, and bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.

Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure. The central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red.

A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer. For example, individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer with some defects causing up to 100% lifetime chance of cancer (e.g. p53 mutations). Such germ line mutations are shown in a box at the left of the figure, with an indication of their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.

The majority of cancers are called non-hereditary or "sporadic cancers". About 30% of sporadic cancers do have some hereditary component that is currently undefined, while the majority, or 70% of sporadic cancers, have no hereditary component.

In sporadic cancers, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. This is indicated in the figure at the 3rd level from the top. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).

When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, more DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.

The somatic mutations and epigenetic alterations caused by DNA damages and deficiencies in DNA repair accumulate in field defects. Field defects are normal appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and improperly proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations.

It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists; for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco, so the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA damaging agents that occur both at the highest concentrations and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene.

Using molecular biological techniques, it is possible to characterize the mutations, epimutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body. However, once a cancer is formed it continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, 59 mutations shared by some, but not all regions, and 29 "private" mutations only present in one region.

The cells in which all these DNA alterations accumulate are difficult to trace, but two recent lines of evidence suggest that normal stem cells may be the cells of origin in cancers. First, there exists a highly positive correlation (Spearman’s rho = 0.81; P < 3.5 × 10−8) between the risk of developing cancer in a tissue and the number of normal stem cell divisions taking place in that same tissue. The correlation applied to 31 cancer types and extended across five orders of magnitude. This correlation means that if the normal stem cells from a tissue divide once, the cancer risk in that tissue is approximately 1X. If they divide 1,000 times, the cancer risk is 1,000X. And if the normal stem cells from a tissue divide 100,000 times, the cancer risk in that tissue is approximately 100,000X. This strongly suggests that the main reason we have cancer is that our normal stem cells divide, which implies that cancer originates in normal stem cells. Second, statistics show that most human cancers are diagnosed in aged people. A possible explanation is that cancers occur because cells accumulate damage through time. DNA is the only cellular component that can accumulate damage over the entire course of a life, and stem cells are the only cells that can transmit DNA from the zygote to cells late in life. Other cells cannot keep DNA from the beginning of life until a possible cancer occurs. This implies that most cancers arise from normal stem cells.

Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair. It is a type of cancer syndrome.