Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

Genetic instabilities in human cancers

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

https://www.unitypoint.org/desmoines/filesimages/Cancer%20Education/Oncology%20Nursing%20Conference/2015/2014%20NCCN%20Clin%20Pract%20Guidelines%20Male%20Sex%20Dysf.pdf

Clinical practice guidelines in oncology

Nonmelanoma skin cancer is the most common cancer in the United States, with over 1.3 million cases expected to occur in the year 2001. Approximately 80 percent of nonmelanoma skin cancers are basal-cell carcinomas, and 20 percent are squamous-cell carcinomas.1 Squamous-cell carcinoma is the second most common cancer among whites.2 Unlike almost all basal-cell carcinomas, cutaneous squamous-cell carcinomas are associated with a substantial risk of metastasis. Incidence In 1994 in the United States, the lifetime risk of squamous-cell carcinoma was 9 to 14 percent among men and 4 to 9 percent among women.3 Although it is known that this neoplasm . . .

Cutaneous Squamous-Cell Carcinoma

• Quantitative frequencies of clinical abnormalities in xeroderma pigmentosum were estimated by abstracting published descriptions of 830 patients in 297 articles obtained from a survey of the medical literature from 1874 to 1982. The median patient age was 12 years with nearly equal numbers of male and female patients. Cutaneous symptoms (sun sensitivity or freckling) had a median age of onset of between 1 and 2 years. Forty-five percent of the patients described had basal cell carcinoma or squamous cell carcinoma of the skin. The median age of first nonmelanoma skin cancer among patients with xeroderma pigmentosum was 8 years, more than 50 years less than that among patients with skin cancer in the United States. Melanomas were reported in 5% of patients. Ninety-seven percent of the reported basal and squamous cell carcinomas and 65% of the melanomas in patients with xeroderma pigmentosum occurred on the face, head, or neck. Seventy percent probability of survival was attained at age 40 years, a 28-year reduction in comparison with the US general population. Ocular abnormalities were reported in 40% of the patients described and were restricted to tissues exposed to ultraviolet radiation (lid, conjunctiva, and cornea) and included ectropion, corneal opacity leading to blindness, and neoplasms. Neurologic abnormalities were found in 18% of the cases reported, consisting of progressive mental deterioration, hyporeflexia or areflexia, and progressive deafness in some patients in association with dwarfism and immature sexual development. There was scant information concerning the efficacy of any therapeutic regimen. (Arch Dermatol1987;123:241-250)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=derm&articleId=548003&pdfFileName=archderm_123_2_026.pdf

Xeroderma Pigmentosum: Cutaneous, Ocular, and Neurologic Abnormalities in 830 Published Cases

Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.

Transcription-coupled DNA repair: two decades of progress and surprises

Xeroderma pigmentosum (XP), is a rare, autosomal recessive disease with sun sensitivity and multiple neoplasms in association with reduced DNA repair. As a reflection of the clinical consequences of deficient DNA repair, XP serves as a model for determining the effects of proficient DNA repair. To estimate the risk of developing neoplasms in XP, we abstracted reports of 726 XP patients (from 41 countries) published from 1874 to 1982. Despite limitations of a literature survey, the XP patients under age 20 years had an estimated 2000-fold increase in frequency of basal cell and squamous cell carcinoma of the skin, of cutaneous melanoma, of cancer of the anterior eye, and of cancer of the anterior tongue, in comparison to the general population. These sites are all potentially exposed to u.v. radiation, a strong carcinogen which produces DNA damage that is poorly repaired by XP cells. XP patients under age 20 years also had an estimated 12-fold increase in occurrence of neoplasms in sites not exposed to u.v. radiation. Among the XP patients under age 40 years with internal cancer, there was a disproportionate representation of malignant neoplasms of the brain (especially sarcomas), and oral cavity (excluding tongue) compared to US whites under age 40 years. These internal neoplasms may be related to exposure to chemical environmental carcinogens that cause DNA damage which, like u.v.-induced damage, is poorly repaired by XP cells. These reports provide no evidence of an increase in XP of common lethal neoplasms such as lymphomas, or female genital tract or endocrine system cancers. These findings suggest that DNA repair plays a role in protection against u.v.-induced neoplasia and in protection against some internal neoplasms in the general population.

Joseph Scotto

Papers

Xeroderma Pigmentosum: Cutaneous, Ocular, and Neurologic Abnormalities in 830 Published Cases

DNA repair protects against cutaneous and internal neoplasia: evidence from xeroderma pigmentosum

Early onset of skin and oral cavity neoplasms in xeroderma pigmentosum